Methods for the administration of certain vmat2 inhibitors

Abstract

Provided are methods for treating cervical dystonia.

Description

METHODS FOR THE ADMINISTRATION OF CERTAIN VMAT2 INHIBITORS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 562,128, filed March 6, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Cervical dystonia (also referred to as neck dystonia or spasmodic torticollis) is an extremely painful, chronic neurological movement disorder where the neck and shoulder muscles contract involuntarily and contort, causing abnormal movements and awkward posture of the head and neck such as the head to twist or turn to the left or right (torticollis), upwards (retrocollis), downwards (antecollis) or sideways (laterocollis). The movements may be sustained (tonic), jerky (clonic), or a combination. Cervical dystonia affects a person's ability to control muscle activity. Cervical dystonia may be primary (meaning that it is the only apparent neurological disorder, with or without a family history) or may be brought about by secondary causes (such as physical trauma) and is often attributed to nervous system damage caused by a stroke, disease or trauma. A rare disorder that can occur at any age, even during infancy, cervical dystonia most often occurs in middle-aged individuals, and is more prevalent in women than men. Those with a family history of cervical dystonia or some other type of dystonia are at higher risk of developing the disorder.

[0003] Treatments for cervical dystonia include oral medications, botulinum toxin injections, surgery, and complementary therapies. The most commonly prescribed treatment for cervical dystonia is the use of botulinum toxin, typically type A (although type B has also been used), which can reduce its signs and symptoms. Botulinum toxin can help block the communication between the nerve and the muscle and may alleviate abnormal movements and postures. The number of injections is typically based on the severity of the dystonia. Doctors injecting the toxin may select the muscles to be injected by observing abnormal postures or movements and feeling for the muscle spasm or by using an electromyography machine to measure muscle activity. Each muscle affected by dystonia typically has to be injected separately.

[0004] Therefore, a major unmet medical need exists for the development of improved therapies. The present invention provides compounds, compositions, and methods to meet these critical needs.BRIEF SUMMARY

[0005] Provided is a method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0006] Also provided is a method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0007] Also provided is a method of adjunctive therapy in a subject with cervical dystonia in need thereof, comprising: administering to the subject a first therapeutically effective amount of (S)-4-((1- therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered a botulinum toxin.

[0008] Also provided is use of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cervical dystonia, wherein optionally the medicament is formulated for treatment with a botulinum toxin.

[0009] Also provided is a pharmaceutical composition comprising (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of cervical dystonia, wherein optionally the treatment further comprises a botulinum toxin.

[0010] These and other aspects of the disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds, and / or compositions, and are each hereby incorporated by reference in their entirety. INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG.1 depicts an overview of the study described in Example 1 conducted with subjects diagnosed with cervical dystonia and treated with botulinum toxin (BTX) for over 6 months.

[0013] FIG.2A is a bar graph showing the effect of valbenazine during the maximum botulinum toxin effectiveness on VAS past week pull scores.

[0014] FIG 2B is a bar graph showing the effect of valbenazine during the maximum botulinum toxin effectiveness on TWSTRS severity scores.

[0015] FIG.2C is a bar graph showing the effect of valbenazine during the maximum botulinum toxin effectiveness on TWSTRS total score.

[0016] FIG.3A is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on TWSTRS pain scores.

[0017] FIG.3B is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on TWSTRS disability scores.

[0018] FIG.3C is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on TWSTRS total scores.

[0019] FIG.4A is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on Neck Pain Disability Index (NPDI) scores.

[0020] FIG.4B is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS 24-hour pain scores.

[0021] FIG.4C is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS 24-hour pull scores.

[0022] FIG.4D is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS 24-hour jerk scores.

[0023] FIG.4E is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS past week pain scores.

[0024] FIG.4F is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS past week pull scores.

[0025] FIG.4G is a bar graph showing the effect of valbenazine during the minimum botulinum toxin effectiveness on VAS past week jerk scores. DETAILED DESCRIPTION Definitions

[0026] 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 disclosure 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.

[0027] 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.

[0028] 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.

[0029] 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 inWO 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,” Verlag 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-1- carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and the like. In some embodiments, “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, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0030] 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. As used herein, the term "approximately” may be used interchangeably with the term “about.”

[0031] In some embodiments, the terms "about" or “approximately”, when used in reference to a degree 2-theta value of an X-ray powder diffraction pattern, refers to + / -0.2 degrees 2- theta.

[0032] As used herein, “co-administer” and “co-administration” and variants thereof mean the administration of at least two drugs (e.g., valbenazine and a co-therapeutic agent) to apatient either sequentially, simultaneously, approximately 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). In some embodiments, the two drugs are administered sequentially in any order. In some embodiments, the two drugs are administered simultaneously or approximately simultaneously. In some embodiments, the two drugs are administered sequentially.

[0033] When co-administered, two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.

[0034] 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.

[0035] 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.

[0036] As used herein, “adjunctive therapy” refers to a treatment that is used in conjunction with a primary treatment. For example, an “adjunctive therapy” may include the administration of valbenazine to a subject in addition to the administration of a botulinum toxin as a primary treatment for cervical dystonia.

[0037] As used herein, “botulinum toxin” refers to a neurotoxin derived from the anaerobic bacterium Clostridium botulinum. Botulinum toxins include but are not limited to Types A, B, C1, C2, D, E, F, and G.

[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, “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.

[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 valbenazine free base, the quantity is the molar equivalent to the corresponding amount of valbenazinefree base. For example, often a drug is packaged in a pharmaceutically acceptable salt form, for example valbenazine ditosylate, and the dosage for strength refers to the mass of the molar equivalent of the corresponding free base, valbenazine. As an example, 73 mg of valbenazine tosylate is the molar equivalent of 40 mg of valbenazine 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 20 to about 160 mg once daily, e.g., about 20, about 40, about 60, about 80, about 100, about 120, or about 160 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, a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.

[0043] 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.

[0044] 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.

[0045] As used herein, “isotopic variant” means a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl),bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen- 14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), and oxygen-18 (18O). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), and oxygen-15 (15O). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, and any oxygen can be18O, as example, where feasible according to the judgment of one of skill in the art. In certain embodiments, an “isotopic variant” of a compound contains an unnatural proportion of deuterium.

[0046] With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or “D” or “d,” it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0047] 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.

[0048] 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.

[0049] As used herein, “Medication Guide” means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications set forth in 21 CFR 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 CFR 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.

[0050] 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.

[0051] As used herein, “patient package insert” means information for patients on how to safely use a pharmaceutical product that is part of the FDA-approved labeling. It is an extension of the professional labeling for a pharmaceutical product that may be distributed to a patient when the product is dispensed which provides consumer-oriented information about the product in lay language, for example it may describe benefits, risks, how to recognize risks, dosage, or administration.

[0052] 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 “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.The term “pharmaceutically acceptable salts” include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, tosylic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine, and the like.

[0053] The phrase “an isotopic variant thereof; or a pharmaceutically acceptable salt thereof” as used herein has the same meaning as the phrase “an isotopic variant; or a pharmaceutically acceptable salt of the compound referenced therein; or an isotopic variant; or a pharmaceutically acceptable salt of an enantiomer or a mixture of enantiomers of the compound referenced therein.”

[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 or EMEA) 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 pop- up window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.

[0058] As used herein, “risk” means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment. An “acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude ofthe risk, and numerous other factors, both political and social. An “acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great. An “unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent. “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0059] As used herein, “safety” means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient- related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).

[0060] 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. In certain embodiments, treating results in improving, maintaining, or lessening the decline of the disorder, disease, or condition, or symptom thereof.

[0061] As used herein, “improving” is meant to mean any appreciable increase in function as measured using standard methodology known in the field. Likewise, as used herein, “maintaining” is meant to mean that there is no significant change in function as measured using standard methodology known in the field. Further, as used herein, “lessening the decline” is meant to mean that there is no appreciable decrease in function as measured using standard methodology known in the field.

[0062] As used herein, “Toronto Western Spasmodic Torticollis Rating Scale” or “TWSTRS” refers to a validated, disease-specific scale in which higher scores indicate greater impairment. It is commonly used in clinical trials of BoNT for the treatment of Cervical Dystonia. The TWSTRS Total (scored 0–85) is composed of the Severity (0– 35), Disability (0−30), and Pain (0−20) subscales. The Toronto Western SpasmodicTorticollis Rating Scale is described in Consky ES, Basinki A, Belle L, Ranawaya R, Lang AE. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS): assessment of validity and inter-rater reliability. Neurology.1990;40(suppl 1):445, the disclosure of which is incorporated herein by reference in its entirety.

[0063] As used herein, “visual analog scale” or “VAS” is a scale to measure subjective responses form subjects based on their perceived levels of pain, spasm, tightness and range of motion from the previous 24 hours.

[0064] As used herein, “Neck Pain Disability Index” or “NPDI” or “NPI” is a patient- completed, condition-specific functional status questionnaire with 10 items including pain, personal care, lifting, reading, headaches, concentration, work, driving, sleeping and recreation. It is the most commonly used self-report measure for neck pain. The Neck Pain Disability Index is described in Vernon H. The Neck Disability Index: state-of-the-art, 1991- 2008. J Manipulative Physiol Ther.2008 Sep;31(7):491-502, the disclosure of which is incorporated herein by reference in its entirety.

[0065] As used herein, the “Pittsburg Sleep Quality Index” or “PSQI” is a patient-completed status questionnaire with 10 items related to the nature and quality of their sleep over the previous 30 days. The questionnaire also includes QOL items related to interruptions to daily routine and general mood due to lack of sleep and / or poor sleep quality. The Pittsburg Sleep Quality Index is described Mollayeva T, Thurairajah P, Burton K, Mollayeva S, Shapiro CM, Colantonio A. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis. Sleep Med Rev. 2016 Feb;25:52-73, the disclosure of which is incorporated herein by reference in its entirety.

[0066] As used herein, the “Investigator Global Assessment of Efficacy” or “IGAE” is a subjective rating system used by the investigator to measure the impact of the investigational treatment on the subject’s overall condition. The IGAE consists of a 4-point scale ranging from 1 (very good) to 4 (poor).

[0067] As used herein, “Patient Evaluation of Global Response” or “PEGR” is a patient- completed descriptive scale ranging from +4 (complete abolishment of signs and symptoms) to −4 (very marked worsening).

[0068] As used herein, “Columbia-Suicide Severity Rating Scale” or “C-SSRS” is a suicidal ideation and behavior rating scale. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent and behaviors."

[0069] As used herein, “head tremor” refers to the involuntary shaking or oscillation of the head of a subject with cervical dystonia. A “head tremor” may be rhythmic or irregular.

[0070] As used herein, “dystonic posturing” refers to the abnormal posture and involuntary muscle contractions of a subject with cervical dystonia.

[0071] As used herein, “reducing the severity of abnormal head position and neck pain” means a subject reports improvement in dystonic posturing of the head and neck and NPDI scores.

[0072] As used herein, “VMAT2” refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from cellular cytosol into synaptic vesicles.

[0073] As used herein, the terms “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibition of VMAT2” refer to the ability of a compound disclosed herein to alter the function of VMAT2. A VMAT2 inhibitor may block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event. The terms and / or phrases “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibition of VMAT2” also refer to altering the function of VMAT2 by decreasing the probability that a complex forms between a VMAT2 and a natural substrate.

[0074] As used herein, “up-titration” of a compound refers to increasing the amount of a compound to achieve a therapeutic effect that occurs before dose-limiting intolerability for the patient. Up-titration can be achieved in one or more dose increments, which may be the same or different. A subject is considered to “tolerate the increased dose” if, for example, any adverse effects experienced by the subject do not outweigh therapeutic effects experienced by the subject. A subject is considered to “not tolerate the increased dose” if, for example, the subject and / or the subject’s physician deem that the adverse effects experienced outweigh any therapeutic effects.

[0075] As used herein, an “adequate response” means the subject has experienced an improvement in one or more symptom of cervical dystonia. Symptoms of cervical dystonia include but are not limited to neck pain, head tremors, dystonic posturing, abnormal head position, and muscle spasms.

[0076] As used herein, “valbenazine” may be referred to as (S)-2-amino-3-methyl-butyric acid (2R, 3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yl ester; or as L-valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10- dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester or as NBI-98854 and has the following chemical structure:.

[0077] A formulation of valbenazine:4-toluenesulfonate (1:2) (referred to herein as “valbenazine ditosylate”) has been previously reported in the FDA approved drug label under the trade name INGREZZA®. A formulation of valbenazine is administered orally to a subject.

[0078] Valbenazine can be prepared according to U.S. Patent Nos.8,039,627 and 8,357,697, the disclosure of each of which is incorporated herein by reference in its entirety. In certain embodiments, the valbenazine for use in the compositions and methods provided herein is in polymorphic Form I as disclosed in U.S. Patent No.10,0659,52, the disclosure of which is incorporated herein by reference in its entirety.Methods of Use

[0079] Provided is a method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising administering to the subject a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

[0080] Provided is a method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising: administering to the subject a therapeutically effective amount of a VMAT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0081] Provided is a method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0082] Provided is a method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0083] Also provided is a method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising: administering to the subject a therapeutically effective amount of a VMAT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0084] Also provided is a method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising administering to the subject a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

[0085] Also provided is a method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0086] Also provided is a method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

[0087] Also provided is a method of adjunctive therapy in a subject with cervical dystonia in need thereof, comprising: administering to the subject a first therapeutically effective amount of (S)-4-((1- therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered a botulinum toxin.

[0088] Also provided is use of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cervical dystonia.

[0089] Also provided is use of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or anisotopic variant thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for adjunctive therapy with a botulinum toxin for the treatment of cervical dystonia.

[0090] Also provided is a pharmaceutical composition comprising (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of cervical dystonia.

[0091] Also provided is a pharmaceutical composition comprising (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, for use in adjunctive therapy with a botulinum toxin for the treatment of cervical dystonia.

[0092] In some embodiments, prior to administration, the subject has moderate to severe head tremor.

[0093] In some embodiments, the botulinum toxin is type A or type B.

[0094] In some embodiments, the botulinum toxin is chosen from onabotulinumtoxinA, rimabotulinumtoxinB, letibotulinumtoxinA, prabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and daxibotulinumtoxinA-lanm.

[0095] In some embodiments, the botulinum toxin is injected.

[0096] In some embodiments, the botulinum toxin is injected into one or more of the affected neck muscles.

[0097] In some embodiments, the one or more of the affected neck muscles is chosen from one or more of the sternocleidomastoid, the splenius capitis, the splenius cervicis, the scalene complex (e.g., the scalenus anterior and / or the scalenus medius), the trapezius (e.g., the upper trapezius), the levator scapulae, the semispinalis capitis, and the longissimus (e.g., longissimus capitis and / or longissimus cervicis).

[0098] In some embodiments, the method further comprises performing electromyography or ultrasound on the subject.

[0099] In some embodiments, prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had been treated with botulinum toxin for at least 6 months.

[0100] In some embodiments, prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) of at least 20.

[0101] In some embodiments, prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline TWSTRS Severity subscale score of at least 10.

[0102] In some embodiments, prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline TWSTRS Disability subscale score greater than or equal to 3.

[0103] In some embodiments, the administration results in a reduction of pain and / or spasm for the subject.

[0104] In some embodiments, the administration results in an improvement of quality of life for the subject.

[0105] In some embodiments, the administration results in an improvement of dystonia as measured by change from baseline in TWSTRS – Total Score.

[0106] In some embodiments, the administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Severity subscale score.

[0107] In some embodiments, the administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Disability subscale score.

[0108] In some embodiments, the administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Pain subscale score.

[0109] In some embodiments, the administration results in an improvement in the subject’s Neck Pain Disability Index (NPDI).

[0110] In some embodiments, the administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for pain.

[0111] In some embodiments, the administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for pulling.

[0112] The method of any one of the preceding claims, wherein said administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for jerking.

[0113] Valbenazine can be administered according to the methods disclosed in U.S. Patent Nos.10,857,137; 10,874,648; 10,912,771; 10,940,141; 10,952,997; 10,857,148; and 10,993,941, the disclosure of each of which is incorporated herein by reference in its entirety.

[0114] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. In a further embodiment, the initial dosage is 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0115] In certain embodiments, the patient is administered a ditosylate salt of (S)-2-amino- 3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-yl ester with an initial dosage of 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base, and the dosage is increased by 20 mg increments every two weeks to a recommended dosage. In a further embodiment, the recommended dosage is 80 mg once daily as measured by (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester free base. In another embodiment, the recommended dosage is 60 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

[0116] In certain embodiments, the patient is monitored for one or more adverse reactions selected from somnolence, akathisia, fatigue, urticaria, rash, nausea and middle insomnia. In a further embodiment, the one or more adverse reactions is selected from somnolence, urticaria and rash.

[0117] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered via a titration scheme that comprises the up-titration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester over a period of no more than about six weeks until an optimized dose is administered.

[0118] In certain embodiments, the titration scheme comprises administering the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof at an initial dose equivalent to about 40 mg of (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily for about two weeks, provided that the subject tolerates the initial dose and that the subject has not had an adequate response, increasing the dose and administering the increased dose to the subject.

[0119] In certain embodiments, the titration scheme comprises administering the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof at an initial dose equivalent to about 40 mg of (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily for about one week, provided that the subject tolerates the initial dose and that the subject has not had an adequate response, increasing the dose and administering the increased dose to the subject.

[0120] In certain embodiments, the increased dose is equivalent to about 60 mg of the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

[0121] In certain embodiments, the increased dose is equivalent to about 80 mg of the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

[0122] In certain embodiments, the titration scheme further comprises administering the (S)- 2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof at the increased dose for about two weeks.

[0123] In certain embodiments, if the subject does not tolerate the increased dose, the optimized dose is the initial dose.

[0124] In certain embodiments, if the subject tolerates the increased dose and if the subject has had an adequate response, the optimized dose is the increased dose.

[0125] In certain embodiments, the methods further comprise administering the optimized dose of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof to the subject.

[0126] In certain embodiments, if the subject tolerates the increased dose and if the subject has not had an adequate response, the method further comprises increasing the dose.

[0127] In certain embodiments, the further increased dose is equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

[0128] In certain embodiments, if the subject does not tolerate the further increased dose, the optimized dose is the increased dose.

[0129] In certain embodiments, if the subject tolerates the further increased dose and if the subject has had an adequate response, the optimized dose is the further increased dose.

[0130] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered in the afternoon or evening.

[0131] In some embodiments, administration of valbenazine orally once daily (QD) as adjunctive treatment in subjects with cervical dystonia, wherein the valbenazine is administered at an initial dose for a period of time followed by a scheduled dose increase. In certain embodiments, the period of time for the initial dose is a week. In certain embodiments, the period of time for the initial dose is two weeks. In certain embodiments, the initial dose is equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base. In certain embodiments, the increased dose is equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base. In certain embodiments, the increased dose is equivalent to about 80 mg of the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0132] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is in a solid dosage form.

[0133] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is orally administered.

[0134] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is in the form of a capsule.

[0135] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered daily.

[0136] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered once daily or twice daily.

[0137] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered once daily.

[0138] In certain embodiments, the therapeutically effective amount is an amount equivalent to from about 10 mg to about 90 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0139] In certain embodiments, the therapeutically effective amount is an amount equivalent to from about 20 mg to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0140] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 20 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0141] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0142] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0143] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0144] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 40 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0145] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 60 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0146] In certain embodiments, the therapeutically effective amount is an amount equivalent to about 80 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base.

[0147] In some embodiments, the VMAT2 inhibitor is chosen from valbenazine, or a pharmaceutically acceptable salt and / or isotopic variant thereof. In some embodiments, the VMAT2 inhibitor is valbenazine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester is a free base. In some embodiments, the VMAT2 inhibitor is (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof. In some embodiments, the VMAT2 inhibitor is deutetrabenazine (i.e., (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one) or a pharmaceutically acceptable salt thereof. In some embodiments, the VMAT2 inhibitor is tetrabenazine (i.e., cis rac –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H- benzo[a]quinolizin-2-one) or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the VMAT2 inhibitor is a valbenazine tosylate salt. In some embodiments, the VMAT2 inhibitor is a ditosylate salt of valbenazine. In certain embodiments, the tosylate salt is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester tosylate salt of structural Formula (I):

[0149] In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt, is in crystalline form. In certain embodiments, the crystalline form is Form I of Formula I.

[0150] In some embodiments, crystalline Form I has a DSC thermogram comprising an endothermic event with an onset temperature of about 240 °C and a peak at about 243 °C

[0151] In certain embodiments, the crystalline form of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt, is Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt having a differential scanning calorimetric (DSC) peak temperature within 2% of 243 °C.

[0152] In certain embodiments, the DSC peak temperature is within 1% of 243 °C.

[0153] In certain embodiments, the DSC peak temperature is within 0.5% of 243 °C.

[0154] In various embodiments, crystalline Form I of (S)-(2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3- methylbutanoate di(4-methylbenzenesulfonate) (Formula I) has an X-ray diffraction pattern. In some embodiments, the X-ray diffraction pattern of Form I of (S)-(2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino- 3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) includes an XRP diffraction peak at two-theta angles of approximately 6.3, 17.9, and 19.7°. In some embodiments, the X- ray powder diffraction pattern of Form I of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4- methylbenzenesulfonate) (Formula I) includes an XRP diffraction peak at two-theta angles of approximately 6.3, 17.9, or 19.7°. In another embodiment, crystalline Form I of (S)- (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) includes an XRP diffraction peak at two-theta angles of approximately 6.3° and 19.7°. Inanother embodiment, crystalline Form I of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4- methylbenzenesulfonate) (Formula I) includes an XRP diffraction peak at two-theta angles of approximately 6.3°.

[0155] In some embodiments, crystalline Form I has one or more characteristic XRP diffraction peaks at two-theta angles of approximately 6.3° and approximately 19.7°. In certain embodiments, crystalline Form I has one or more characteristic XRP diffraction peaks at two-theta angles of approximately 6.3°, approximately 17.9°, and approximately 19.7°. In some embodiments, crystalline Form I has one or more characteristic XRP diffraction peaks at two-theta angles of approximately 6.3°, approximately 17.9°, approximately 19.7°, and approximately 22.7°. In certain embodiments, crystalline Form I has one or more characteristic XRP diffraction peaks at two-theta angles of approximately 6.3°, approximately 15.6°, approximately 17.9°, approximately 19.7°, and approximately 22.7°. In some embodiments, crystalline Form I has one or more characteristic XRP diffraction peaks at two-theta angles of approximately 6.3°, approximately 15.6°, approximately 16.6°, approximately 17.9°, approximately 19.7°, and approximately 22.7°. In certain embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 6.3°±0.2°. In certain embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 17.9°±0.2°. In certain embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 19.7°±0.2°.

[0156] In yet another embodiment, crystalline Form I has a thermal gravimetric analysis (TGA) plot comprising a mass loss of less than about 0.4% when heated from about 25 °C to about 140 °C.

[0157] In various embodiments, crystalline Form I has a gravimetric vapor system (GVS) plot. In some embodiments, crystalline Form I exhibit a mass increase of about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity. In certain embodiments mass gained upon adsorption is lost when the relative humidity (RH) is decreased back to about 0% RH. In still another embodiment, crystalline Form I is stable upon exposure to about 25 °C and about 60% relative humidity. In yet another embodiment, crystalline Form I is stable upon exposure to about 25 °C and about 60% relative humidity for about 24 months. Also in another embodiment, crystalline Form I is stable upon exposure to about 25 °C and about 60% relative humidity for about 3 months. In still another embodiment, crystalline Form I is stable upon exposure to about 25 °C and about 92%relative humidity. In another embodiment, crystalline Form I is stable upon exposure to about 40 °C and about 75% relative humidity. In another embodiment, crystalline Form I is stable upon exposure to about 40 °C and about 75% relative humidity for about 6 months. In another embodiment, crystalline Form I is stable upon exposure to about 40 °C and about 75% relative humidity for about 3 months.

[0158] In certain embodiments, crystalline form of Formula I in Form I may contain no less than about 95%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5% by weight of the salt of Formula I. The crystalline form may also contain no less than about 90%, no less than about 95%, no less than about 98%, no less than about 99%, or no less than 99.5% by weight of crystal Form I.

[0159] In certain embodiments, the crystalline form has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt.

[0160] In certain embodiments, the crystalline form has a purity of no less than 98% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt.

[0161] In certain embodiments, the crystalline form has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt; and has an X- ray powder diffraction (XRPD) pattern comprising peaks at two-theta angles of 6.3°±0.2°, 17.9°±0.2°, and 19.7°±0.2°.

[0162] In certain embodiments, crystalline Form I has an aqueous solubility of about 17.58, about 18.58, about 19.58, about 26.75, about 26.87, about 26.96, about 27.06, about 27.75, about 27.87, about 27.97, about 28.06, about 28.75, about 28.87, about 28.97, about 29.06, about 27.45, about 28.45, about 29.45, about 30.61, about 31.61, about 32.61, about 32.17, about 32.98, about 33.17, about 33.98, about 34.17, about 34.35, about 34.98, about 35.35, or about 36.35 mg / mL. In certain embodiments, crystalline Form I has an aqueous solubility of about 31.61 and about 33.17 at approximately pH 1.2; about 28.45 and about 27.97 at approximately pH 3; about 28.06 and about 27.77 at approximately pH 4; about 18.58 and about 27.87 at approximately pH 5; or about 33.98 and about 35.35 at approximately pH 6.8.

[0163] In certain embodiments, crystalline Form I may contain no greater than about 0.1%, no greater than about 0.11%, no greater than about 0.12%, no greater than about 0.13%, no greater than about 0.14%, no greater than about 0.15%, no greater than about 0.16%, no greater than about 0.17%, no greater than about 0.18%, no greater than about 0.19%, nogreater than about 0.2%, no greater than about 0.21%, no greater than about 0.22%, no greater than about 0.23%, no greater than about 0.24%, no greater than about 0.25%, no greater than about 0.26%, no greater than about 0.27%, no greater than about 0.28%, no greater than about 0.29%, no greater than about 0.3%, no greater than about 0.31%, no greater than about 0.32%, no greater than about 0.33%, no greater than about 0.34%, no greater than about 0.35%, no greater than about 0.36%, no greater than about 0.37%, no greater than about 0.38%, no greater than about 0.39%, no greater than about 0.4%, no greater than about 0.5%, no greater than about 0.6%, no greater than about 0.7%, no greater than about 0.8%, no greater than about 0.9%, no greater than about 1%, no greater than about 2%, no greater than about 3%, no greater than about 4%, or no greater than about 5% water by weight.

[0164] In certain embodiments Form I may be characterized by particle analysis. In certain embodiments, a sample of Form I comprises particles having rhomboid crystal morphology. In yet another embodiment, a sample of Form I comprises particles of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, or about 5 μM in length. In some embodiments, a sample of Form I comprises particles of about 70, about 60, about 40, about 20, or about 10 μM in length. In other embodiments, a sample of Form I comprises particles of about 69.39, about 56.22, about 34.72, about 17.84, or about 10.29 μM in length.

[0165] In certain embodiments, the crystalline form has a D90 particle size of about 70 μM in length. As used herein, a “D90 particle size” refers to the value of the particle diameter at which about 90% of the particles in a sample have a value that is lower than the D90 value, and about 10% of the particles in the sample have a value that is higher than the D90 value.

[0166] In certain embodiments, the crystalline form has a D10 particle size of about 10 μM in length. As used herein, a “D10 particle size” diameter distribution refers to the value of the particle diameter at which about 10% of the particles in a sample have a value that is lower than the D10 value, and about 90% of the particles in the sample have a value that is higher than the D90 value.

[0167] The average diameter and particle diameter distribution of solid forms described herein can be measured using conventional particle size analysis techniques (e.g., sieve analysis, laser diffraction analysis, or microscope counting). Additional methods of measurement are described in U.S. Pharmacopeia (“USP”) 905 (Uniformity of Dosage Units (2016)) and USP 429 (Light Diffraction Measurement of Particle Size (2016)), each of which is incorporated herein by reference for all purposes.

[0168] In some embodiments, provided herein is method for treating cervical dystonia, wherein the patient is also being administered a strong cytochrome P4502D6 (CYP2D6) inhibitor, comprising: orally administering once daily to the patient (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, in an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

[0169] In some embodiments, provided herein is a method for treating cervical dystonia, wherein the patient is a cytochrome P4502D6 (CYP2D6) poor metabolizer, comprising: orally administering once daily to the patient (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, in an amount of equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)- 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

[0170] In some embodiments, provided herein is a method for treating cervical dystonia, comprising: (a) orally administering to the patient a therapeutically effective amount of (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof; (b) subsequently determining that the patient is a cytochrome P4502D6 (CYP2D6) poor metabolizer; and (c) reducing dosage of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof administered to the patient to an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)- 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

[0171] In some embodiments, provided herein is a method for treating cervical dystonia, comprising: determining if the patient is a poor metabolizer of cytochrome P4502D6 (CYP2D6); and if the patient is a poor metabolizer of cytochrome P4502D6 (CYP2D6), then orally administering to the patient a first therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, wherein the first therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester; or if the patient is not a poor metabolizer of cytochrome P4502D6 (CYP2D6), then orally administering to the patient a second therapeutically effective amount of (S)-2-amino- 3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, wherein the second therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester for one week, and subsequently administering an increased amount of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or pharmaceutically acceptable salt thereof after one week.

[0172] In some embodiments, provided herein is a method for treating cervical dystonia, comprising: (a) orally administering to the patient a therapeutically effective amount of a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, wherein the therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester; (b) subsequently determining that the patient is a poor metabolizer of cytochrome P4502D6 (CYP2D6); and (c) administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient.

[0173] In some embodiments, provided herein is a method for treating cervical dystonia, wherein the patient is a cytochrome P4502D6 (CYP2D6) poor metabolizer, comprising: orally administering once daily to the patient a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof.

[0174] In some embodiments, provided herein is a method of administering (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester, or a pharmaceutically acceptable salt thereof, or an isotopic variant thereof, to a patient in need thereof, wherein the patient is being treated with a strong cytochrome P4503A4 (CYP3A4) inducer, comprising: discontinuing treatment of the strong CYP3A4 inducer and then administering the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester to the patient, thereby avoiding the use of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester in combination with the strong CYP3A4 inducer.

[0175] In some embodiments, provided herein is a method for treating cervical dystonia in a patient in need thereof, wherein the patient is being administered a strong cytochrome P450 3A4 (CYP3A4) inducer, comprising: discontinuing treatment of the strong CYP3A4 inducer, and then orally administering once daily to the patient a therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, thereby avoiding the concomitant use of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester with the strong CYP3A4 inducer.

[0176] In some embodiments, provided herein is a method for treating cervical dystonia, wherein the patient is also being administered a strong cytochrome P4503A4 (CYP3A4) inhibitor, comprising: orally administering once daily to the patient (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, in an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

[0177] In some embodiments, provided herein is a method for treating cervical dystonia in a patient, comprising: (a) orally administering to the patient a therapeutically effective amount of (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof; (b) subsequently determining that the patient is being administered a strong cytochrome P4503A4 (CYP3A4) inhibitor; and (c) reducing dosage of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester administered to the patient to an amount equivalent to about 40 mg as measured by (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily.

[0178] In some embodiments, provided herein is a method for treating cervical dystonia in a patient, comprising: (a) orally administering to the patient a therapeutically effective amount of a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)- 2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily; (b) subsequently determining that the patient is being administered a strong cytochrome P4503A4 (CYP3A4) inhibitor; and (c) administering the same therapeutically effective amount of the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester to the patient.

[0179] In some embodiments, provided herein is a method for treating cervical dystonia, wherein the patient is also being co-administered digoxin, comprising: (a) administering to the patient a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3 sobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester, or a pharmaceutically acceptable salt or isotopic variant thereof, (b) monitoring the digoxin concentration in the patient's blood; and (c) reducing the dose of digoxin when the digoxin exposure in the patient's blood is increased as compared with the digoxin level in a patient who is administered digoxin alone.

[0180] In some embodiments, provided herein is a method for treating cervical dystonia, wherein the patient is also in need of treatment with digoxin, the method comprising:orally administering to the patient a therapeutically effective amount of a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, and administering the digoxin to the patient at a reduced dose to compensate for the expected increase in exposure resulting from co-administration of the digoxin and the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10- dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, wherein the reduced dose is relative to what the patient would be administered if the patient is not being administered the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester.

[0181] In some embodiments, a method for treating cervical dystonia, comprising administering to a subject in need thereof a therapeutically effective amount of (S)-2-amino- 3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro- 2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered at least one co- therapeutic agent for the treatment of cervical dystonia is provided herein.

[0182] In some embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester is administered via a titration scheme that comprises the up-titration of the (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester over a period of no more than about six weeks until an optimized dose is administered.

[0183] In some embodiments, the titration scheme comprises administering the (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester at an initial dose equivalent to about 40 mg of valbenazine free base once daily for about two weeks, provided that the patient tolerates the initial dose and that the patient has not had an adequate response, increasing the dose, and administering the increased dose to the patient.

[0184] In some embodiments, the increased dose is equivalent to about 60 mg of valbenazine free base once daily.

[0185] In some embodiments, the titration scheme further comprises administering the (S)- 2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester at said increased dose for about two weeks.

[0186] In some embodiments, if the patient does not tolerate the increased dose, the optimized dose is the initial dose.

[0187] In some embodiments, if the patient tolerates the increased dose and if the patient has had an adequate response, the optimized dose is the increased dose.

[0188] In some embodiments, the method further comprises administering the optimized dose of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester to the patient.

[0189] In some embodiments, if the patient tolerates the increased dose and if the patient has not had an adequate response, the method further comprises increasing the dose.

[0190] In some embodiments, the further increased dose is equivalent to about 80 mg of valbenazine free base once daily.

[0191] In some embodiments, if the patient does not tolerate the further increased dose, the optimized dose is the increased dose.

[0192] In some embodiments, if the patient tolerates the further increased dose and if the patient has had an adequate response, the optimized dose is the further increased dose.

[0193] In some embodiments, the method further comprises administering the optimized dose of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester to the patient.

[0194] In one embodiment, provided herein is a method for treating cervical dystonia, comprising administering to a subject a therapeutically effective amount of (S)- (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) in an amorphous form, or crystalline Form I, II, III, IV, V, or VI; or an isotopic variant thereof; or solvate thereof.

[0195] In one embodiment, provided herein is a method for treating cervical dystonia, comprising administering to a subject a therapeutically effective amount of (S)- (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1- a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride (Formula II) in an amorphous form, or crystalline Form I, or II; or an isotopic variant thereof; or solvate thereof. PHARMACEUTICAL COMPOSITIONS

[0196] Also provided is a composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or apharmaceutically acceptable salt and / or isotopic variant thereof, comprising a therapeutically effective amount of the VMAT2 inhibitor.

[0197] Also provided is a composition for treating a patient in need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from (RR, SS)-1, 3, 4, 6, 7, 11b- hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one and 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one or a pharmaceutically acceptable salt thereof.

[0198] In certain embodiments, the composition is for treating a neurological or psychiatric disease or disorder. In certain embodiments, the neurological or psychiatric disease or disorder is cervical dystonia.

[0199] In certain embodiments, the composition is administered in an amount equivalent to from about 20 mg to about 120 mg of valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 20 mg of valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 40 mg of valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 80 mg of valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 60 mg of valbenazine free base of the VMAT2 inhibitor. In certain embodiments, the composition is administered in an amount equivalent to about 120 mg of valbenazine free base of the VMAT2 inhibitor.

[0200] In certain embodiments, the composition is administered for a first period of time in a first amount of the VMAT2 inhibitor and then the amount is increased to a second amount. In certain embodiments, the first period of time is a week. In certain embodiments, the first amount is equivalent to about 40 mg of valbenazine free base. In certain embodiments, the second amount is equivalent to about 80 mg of valbenazine free base.

[0201] Also provided herein is a pharmaceutical composition for use in treating neurological or psychiatric disease or disorders, comprising the VMAT2 inhibitor as an active pharmaceutical ingredient, in combination with one or more pharmaceutically acceptable carriers or excipients.

[0202] The choice of excipient, to a large extent, depends on factors, such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0203] The pharmaceutical compositions provided herein may be provided in unit dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0204] Also provided herein are pharmaceutical compositions of valbenazine that are suitable for oral administration by sprinkling onto soft foods. In certain embodiments, the pharmaceutical dosage form comprises a plurality of granules. In certain embodiments, each granule comprises an average diameter of at least 1 mm. In certain embodiments, each granule comprises at least one pharmaceutically acceptable carrier and an amount of valbenazine, or a pharmaceutically acceptable salt thereof (e.g., valbenazine ditosylate). In certain embodiments, each granule comprises a film-coating. In certain embodiments, the film-coating comprises a film-forming polymer such as poly(vinyl alcohol). In certain embodiments, the film-coating comprises a plasticizer such as polyethylene glycol, glycerin, or a mixture thereof. In certain embodiments, the film-coating comprises a filler such as talc. In certain embodiments, the film-coating comprises a pigment / opacifier such as titanium dioxide. In certain embodiments, the film-coating comprises OPADRY® II. In certain embodiments, the film-coating comprises a diluent such as silicified microcrystalline cellulose, isomalt, or a mixture thereof. In certain embodiments, the at least one pharmaceutically acceptable carrier comprises a disintegrant such as partially pregeletanized maize starch. In certain embodiments, the at least one pharmaceutically acceptable carrier comprises a binder, such as hydroxypropyl methylcellulose (also referred to as hypromellose). In certain embodiments, the at least one pharmaceutically acceptable carrier comprises a lubricant such as magnesium stearate.

[0205] In some embodiments, the pharmaceutical dosage form is a capsule. In some embodiments, the capsule is a size 00 or smaller. In some embodiments, the capsule is a size 00. In some embodiments, the capsule is a size 0 or smaller. In some embodiments, the capsule is a size 0. In some embodiments, the capsule is a size 1 or smaller. In someembodiments, the capsule is a size 1. In some embodiments, the capsule is a size 2. In some embodiments, the capsule is a size 2 or smaller. In some embodiments, the capsule is a sprinkle capsule. As used herein, “capsule size” refers to the internationally accepted numbering system for capsule sizes used in approved U.S. drug products.

[0206] The pharmaceutical compositions provided herein may be administered alone, or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art). The pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Oral Administration

[0207] The pharmaceutical compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.

[0208] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to,starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

[0209] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0210] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Vee gum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[0211] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc;hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL®200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant. Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc. Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water- soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0212] It should be understood that many carriers and excipients may serve several functions, even within the same formulation. The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by asugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[0213] The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[0214] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

[0215] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term “lower” means an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirsare clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0216] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or polyalkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750- dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0217] The pharmaceutical compositions provided herein for oral administration may be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.

[0218] The pharmaceutical compositions provided herein may be provided as noneffervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. Coloring and flavoring agents can be used in all of the above dosage forms. The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

[0219] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as antacids, proton pump inhibitors, and H2-receptor antagonists. Dosages

[0220] In the treatment of conditions, disorders or diseases associated with VMAT2 inhibition, an appropriate dosage level generally is about 0.001 to 100 mg per kg patient bodyweight per day (mg / kg per day), about 0.01 to about 80 mg / kg per day, about 0.1 to about 50 mg / kg per day, about 0.5 to about 25 mg / kg per day, or about 1 to about 20 mg / kg per day, which may be administered in single or multiple doses. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0, 1 to 15, 1 to 20, or 1 to 50 mg / kg per day. In certain embodiments, the dosage level is about 0.001 to 100 mg / kg per day.

[0221] In certain embodiments, the dosage level is about from 20 to 100 mg / kg per day. In certain embodiments, the dosage level is about 0.01 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 50 mg / kg per day. In certain embodiments, the dosage level is about 0.1 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 0.5 to about 25 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 80 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 75 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 50 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 40 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 25 mg / kg per day. In certain embodiments, the dosage level is about 1 to about 20 mg / kg per day.

[0222] In certain embodiments, the dosage level is about from 5.0 to 150 mg per day, and in certain embodiments from 10 to 100 mg per day. In certain embodiments, the dosage level is about 80 mg per day. In certain embodiments, the dosage level is about 40 mg per day.

[0223] For oral administration, the pharmaceutical compositions can be provided in the form of tablet or capsule containing 1.0 to 1,000 mg of the active ingredient, particularly about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 75, about 80, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 100 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 80 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 60 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be providedin the form of tablet or capsule containing about 50 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 40 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 20 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 25 mg of the active ingredient. In certain embodiments, the pharmaceutical compositions can be provided in the form of tablet or capsule containing about 20 mg of the active ingredient. The compositions may be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day. In certain embodiments, the pharmaceutical compositions are administered on a regimen of once per day.

[0224] It will be understood, however, that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0225] The compounds provided herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of the diseases or conditions for which the compounds provided herein are useful.

[0226] Such other agents, or drugs, may be administered, by a route and in an amount commonly used thereof, simultaneously, or sequentially with the compounds provided herein. When compounds provided herein are used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds provided herein may be utilized but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to the compounds provided herein.

[0227] The weight ratio of the compounds provided herein to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when the compounds provided herein are used in combination with the second drug, or a pharmaceutical composition containing such other drug, the weight ratio of the particulates to the second drug may range from about 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.

[0228] Combinations of the particulates provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0229] In certain embodiments, the VMAT2 inhibitor is administered orally.

[0230] In certain embodiments, the VMAT2 inhibitor is administered in the form of a capsule.

[0231] In certain embodiments, the VMAT2 inhibitor is administered with or without food.

[0232] Exemplary 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. EXAMPLES Example 1

[0233] An open-label, prospective study of subjects with an established clinical diagnosis of cervical dystonia with moderate to severe head tremor and dystonic posturing currently being treated with botulinum toxin (BTX) for >6 months was conducted.

[0234] Inclusion criteria were: • Male or female patients between 18 and 85 years of age (inclusive) • A clinical diagnosis of cervical dystonia (ie, spasmodic torticollis) by investigator for at least six months • Moderate to severe head tremor and / or dystonic posturing as judged by the investigator • Stable Botulinum Toxin (onabotulinumtoxinA sold under the trademark BOTOX® by Allergan, Inc., abobotulinumtoxinA sold under the trademark DYSPORT® by Ipsen Biopharm Limited, incobotulinumtoxinA sold under the trademark XEOMIN® by Merz North America, Inc., or rimabotulinumtoxinB sold under the trademark MYOBLOC® by Solstice Neurosciences, Inc.) therapy dosage for at least 3 months prior to baseline visit

[0235] Exclusion criteria were: • Tardive dyskinesia • Predominant anterocollis• Concomitant use of strong CYP3A4 inhibitors (i.e. itraconazole, ketoconazole, clarithromycin), digoxin, strong CYP2D6 inhibitors (i.e. paroxetine, fluoxetine, quinidine), monoamine oxidase inhibitors (i.e. isocarboxazid, phenelzine, selegiline) • Myotomy or denervation surgery in the affected muscles (eg, peripheral denervation and / or spinal cord stimulation) • Diagnosis of Myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, or any other significant neuromuscular disease which might interfere with the trial • Moderate to severe hepatic impartment as determined by a Child-Hugh Score ≥7 • Marked limitation on passive range of motion that suggests contractures or other structural abnormality, e.g., cervical contractures or cervical spine syndrome • Any conditions that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into the study • Participation in another interventional study during participation in the study • Pregnant or lactating females, or females of child-bearing potential not willing to use an acceptable method of contraception • Is suicidal at screening as defined by below: o a. According to the C-SSRS, he or she must not be actively suicidal at Visit 1 (Screening) or Visit 2 (Baseline) (including, an answer of “yes” to C-SSRS questions 4 or 5 [current or over the last 6 months]) and must not have attempted suicide in the 1 year prior to Visit 1 (Screening); OR o b. The subject is actively suicidal in the Investigator’s judgment

[0236] The regular duration of observation and data collection for an individual patient was a period of 4 weeks of baseline evaluation followed by 12 weeks of on investigational product. Subjects received 40 mg valbenazine daily for 4 weeks. Dose was titrated to 80mg daily beginning at 8 weeks if IP was tolerated by the subjects – if not, the subject remained or was titrated down to 40mg daily for the duration of the study. Subjects continued to receive standard botulin toxin injection per their routine standard of care throughout the study.

[0237] The primary endpoint was the change in incidence rate of pain / spasm as measured by frequency and intensity in subjects prior to and during use of valbenazine as measured byToronto Western Spasmodic Torticollis Rating Scale (TWSTR) and IMU. An overview of the study is provided in FIG.1.

[0238] Secondary endpoints were: • Changes in Twenty-four-hour pain / spasm / tightness / range of motion visual analog scale (VAS 0-10) for pain, pulling, and jerking • Changes in Neck Pain Disability Index (NPDI) • Changes in Sleep quality as measured by The Pittsburg Sleep Quality Index (PSQI) • Treatment efficacy as measured by Investigator Global Assessment of Efficacy (IGAE) • Treatment efficacy as measured by Patient Evaluation of Global Response (PEGR) to assess severity, pain, disability, pulling, jerking, and sleep quality.

[0239] 13 subjects (7 females and 6 males) between 46 and 84 years (mean age 65.23) were enrolled and followed for a total of 16 weeks. Evaluations were performed four weeks prior to the subject’s scheduled BTX treatment (time 1) while on no valbenazine compared to four weeks prior to the subjects next round of BTX while on drug (time 4). A second comparison was made between the BTX injection date and dispensing of valbenazine (time 2) and the next BTX injection date while on drug (time 5).

[0240] Specific dosages and adverse events are shown in the tables below: Dosage DescriptivesAdverse Events Descriptives

[0241] TWSTRS total and severity subset scores were significantly improved at time 4 compared to time 1 (p=0.01), as well as VAS pulling (p=0.02) TWSTRS total, pain, anddisability subset scores, NPDI, and VAS for pain, pulling, and jerking were all significantly improved at time 5 compared to time 2 (p=0.01). The medication was tolerated well with fatigue as the most common adverse effect.

[0242] Overall group results at Time 1 and Time 4 are shown below. VAS Past Week Pull showed a significant decrease from time 1 to time 4 p=0.02 with a large effect size (FIG.2A). TWSTRS Severity significant decreased from time 1 to time 4 p=0.01 with a large effect size (FIG.2B). TWSTRS Total significant decreased from time 1 to time 4 p=0.01 with a large effect size (FIG.2C). “*” indicates a significant difference between timepoints.

[0243] Overall group results at Time 2 and Time 5 are shown below. Significant decreases were found in NPDI (p=0.01), VAS 24 Pain (p=0.01), VAS 24 Pull (p=0.01), VAS 24 Jerk (p=0.01), VAS Past Wk Pain (p=0.01), VAS Past Wk Pull (p=0.01), VAS Past Wk Jerk (p=0.01), TWSTRS Pain (p=0.01), TWSTRS Disability (p=0.01), and TWSTRS Total (p=0.01) from time 2 to time 5 (FIGs.4A, 4B, 4C, 4D, 4E, 4F, 4G, 3A, 3B, 3C, respectively). “*” indicates a significant difference between timepoints.

[0244] Results for TWSTRS Pain Group Time 1 and Time 4 (High >10, Low 9.9 & lower) are shown below. Results for NPDI were significant; those with high pain had a significant decrease at Time 4 (p=0.01).

[0245] Results for TWSTRS Pain Group Time 1 and Time 4 (High >10, Low 9.9 & lower) are shown below. Results for VAS Pain Past Wk were significant; those with high pain have a significant decrease at Time 4 (p=0.01)

[0246] Results for TWSTRS Pain Group Time 1 and Time 4 (High >10, Low 9.9 & lower) are shown below. Results for TWSTRS Severity were significant; those with high pain have a significant decrease at Time 4 (p=0.02). For TWSTRS Total, those with high pain had a significant decrease at Time 4 (p=0.03).

[0247] Results for TWSTRS Pain Group Time 2 and Time 5 (High >10, Low 9.9 & lower) are shown below. Results for NPDI were significant; those with high pain had a significant decrease at Time 5 (p=0.03).

[0248] Results for TWSTRS Pain Group Time 2 and Time 5 (High >10, Low 9.9 & lower) are shown below. Results for VAS Jerk Past Wk were significant; those with high pain have a significant decrease at Time 5 (p=0.03).

[0249] Results for TWSTRS Pain Group Time 2 and Time 5 (High >10, Low 9.9 & lower) are shown below. For TWSTRS Total, those with high pain had a significant decrease at Time 5 (p=0.04).

[0250] Results for TWSTRS Total Group Time 1 and Time 4 (High >35, Low 34 & lower) are shown below. There were no significant differences.

[0251] Results for TWSTRS Total Group Time 1 and Time 4 (High >35, Low 34 & lower) are shown below. Results for VAS Pain Past Wk were significant; those with high pain have a significant decrease at Time 4 (p=0.01).

[0252] Results for TWSTRS Total Group Time 1 and Time 4 (High >35, Low 34 & lower) are shown below. Results for TWSTRS Severity were significant; those with high pain have a significant decrease at Time 4 (p=0.02). For TWSTRS Pain, those with high pain had a significant decrease at Time 4 (p=0.02).

[0253] Results for TWSTRS Overall Group Time 2 and Time 5 (High >35, Low 34 & lower) are shown below. Results for NPDI were significant; those with high pain have a significant decrease at Time 5 (p=0.01). Results for VAS 24 Pain were significant; those with high pain have a significant decrease at Time 5 (p=0.01). Results for VAS 24 Pull were significant; those with high pain have a significant decrease at Time 5 (p=0.01).

[0254] Results for TWSTRS Overall Group Time 2 and Time 5 (High >35, Low 34 & lower) are shown below. Results for VAS Pain Past Wk were significant; those with high pain have a significant decrease at Time 5 (p=0.01). Results for VAS Pull Past Wk were significant; those with high pain have a significant decrease at Time 5 (p=0.03). Results for VAS Jerk Past Wk were significant; those with high pain have a significant decrease at Time 5 (p=0.02).

[0255] Results for TWSTRS Overall Group Time 2 and Time 5 (High >35, Low 34 & lower) are shown below. For TWSTRS Pain; those with high pain had a significant decrease at Time 5 (p=0.01). For TWSTRS Disability, those with high pain had a significant decrease at Time 5 (p=0.01).

[0256] No significant improvements were seen in the PSQI, IGAE, or PEGR as shown below.Example 2: Formulations / Study Medications

[0257] The composition of 20, 40, 60, and 80 mg dose strength valbenazine is provided in the tables below. Formulation 1: Quantitative Composition of Valbenazine Capsules, 20, 40, 60, and 80 mg (Free Base Equivalent)Formulation 2: Quantitative Composition of Valbenazine Capsules, 40 mg (Free Base Equivalent)

[0258] Although the disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. The various embodiments described above can be combined to provide further embodiments. All of the 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.

[0259] 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 be 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

WHAT IS CLAIMED IS:

1. A method for the treatment of cervical dystonia in a subject in need thereof wherein the subject has at least one symptom chosen from severe pain, head tremor and dystonic posturing comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

2. A method for reducing the severity of abnormal head position and neck pain in a subject having cervical dystonia in need thereof, comprising: administering to the subject a therapeutically effective amount of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein optionally, the subject is also being administered a botulinum toxin for the treatment of cervical dystonia.

3. A method of adjunctive therapy in a subject with cervical dystonia in need thereof, comprising: administering to the subject a first therapeutically effective amount of (S)-4-((1- therapeutically effective amount of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3- isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein the subject is also being administered a botulinum toxin.

4. The method of any one of the preceding claims, wherein, prior to administration, the subject has moderate to severe head tremor.

5. The method of any one of the preceding claims, wherein the botulinum toxin is type A or type B.

6. The method of claim 5, wherein the botulinum toxin is chosen from onabotulinumtoxinA. rimabotulinumtoxinB, letibotulinumtoxinA, prabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and daxibotulinumtoxinA-lanm.

7. The method of any one of the preceding claims, wherein the botulinum toxin is injected.

8. The method of claim 6, wherein the botulinum toxin is injected into one or more of an affected neck muscle of the subject having cervical dystonia.

9. The method of claim 7, wherein the one or more of the affected neck muscles is chosen from one or more of the sternocleidomastoid, the splenius capitis, the splenius cervicis, the scalene complex, the trapezius, the levator scapulae, the semispinalis capitis, and the longissimus.

10. The method of any one of the preceding claims, further comprising performing electromyography or ultrasound on the subject.

11. The method of any one of the preceding claims, wherein prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had been treated with botulinum toxin for at least 6 months.

12. The method of any one of the preceding claims, wherein prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) of at least 20.

13. The method of any one of the preceding claims, wherein prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline TWSTRS Severity subscale score or at least 10.

14. The method of any one of the preceding claims, wherein prior to administration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, the subject had cervical dystonia with moderate severity as measured by a baseline TWSTRS Disability subscale score greater than or equal to 3.

15. The method of any one of the preceding claims, wherein said administration results in a reduction of pain and / or spasm for the subject.

16. The method of any one of the preceding claims, wherein said administration results in an improvement of quality of life for the subject.

17. The method of any one of the preceding claims, wherein said administration results in an improvement of dystonia as measured by change from baseline in TWSTRS – Total Score.

18. The method of any one of the preceding claims, wherein said administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Severity subscale score.

19. The method of any one of the preceding claims, wherein said administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Disability subscale score.

20. The method of any one of the preceding claims, wherein said administration results in an improvement of dystonia as measured by change from baseline in TWSTRS Pain subscale score.

21. The method of any one of the preceding claims, wherein said administration results in an improvement in the subject’s Neck Pain Disability Index (NPDI).

22. The method of any one of the preceding claims, wherein said administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for pain.

23. The method of any one of the preceding claims, wherein said administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for pulling.

24. The method of any one of the preceding claims, wherein said administration results in an improvement in the subject’s visual analog scale (VAS, 0-10) for jerking.

25. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered via a titration scheme that comprises the up-titration of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2, 1-a]isoquinolin-2-yl ester over a period of no more than about six weeks until an optimized dose is administered.

26. The method of claim 25, wherein the titration scheme comprises administering the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof at an initial dose equivalent to about 40 mg of (S)-2- amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily for about two weeks, provided that the subject tolerates the initial dose and that the subject has not had an adequate response, increasing the dose and administering the increased dose to the subject.

27. The method of claim 26, wherein the increased dose is equivalent to about 60 mg of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

28. The method of claim 26, wherein the increased dose is equivalent to about 80 mg of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

29. The method of any one of claims 25 to 28, wherein the titration scheme further comprises administering the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof at the increased dose for about two weeks.

30. The method of any one of claims 25 to 28, wherein if the subject does not tolerate the increased dose, the optimized dose is the initial dose.

31. The method of claim 29, wherein if the subject tolerates the increased dose and if the subject has had an adequate response, the optimized dose is the increased dose.

32. The method of claim 30 or 31, further comprising administering the optimized dose of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof to the subject.

33. The method of claim 29, wherein if the subject tolerates the increased dose and if the subject has not had an adequate response, the method further comprises increasing the dose.

34. The method of claim 33, wherein the further increased dose is equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester free base once daily.

35. The method of claim 33 or 34, wherein if the subject does not tolerate the further increased dose, the optimized dose is the increased dose.

36. The method of claim 33 or 34, wherein if the subject tolerates the further increased dose and if the subject has had an adequate response, the optimized dose is the further increased dose.

37. The method of claim 35 or 36, further comprising administering the optimized dose of the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof to the subject.

38. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is in a solid dosage form.

39. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is orally administered.

40. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is in the form of a capsule.

41. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered daily.

42. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered once daily or twice daily.

43. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered once daily.

44. The method of claim 43, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof is administered in the afternoon or evening.

45. The method of any one of the preceding claims, wherein the therapeutically effective amount is an amount equivalent to from about 10 mg to about 90 mg of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester free base.

46. The method of any one of the preceding claims, wherein the therapeutically effective amount is an amount equivalent to from about 20 mg to about 80 mg of (S)-2-amino-3- methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester free base.

47. The method of any one of the preceding claims, wherein the therapeutically effective amount is an amount equivalent to about 20 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

48. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 40 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

49. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 60 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

50. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 80 mg of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

51. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 40 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

52. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 60 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

53. The method of any one of claims 1 to 46, wherein the therapeutically effective amount is an amount equivalent to about 80 mg / day of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester free base.

54. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester is a free base.

55. The method of any one of claims 1 to 53, wherein the (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester is a salt.

56. The method of claim 55, wherein the salt is a tosylate salt.

57. The method of claim 56, wherein the tosylate salt is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1- a]isoquinolin-2-yl ester tosylate salt of structural Formula (I):

58. The method of any one of the preceding claims, wherein the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt, is in crystalline form.

59. The method of claim 58, wherein the crystalline form of the (S)-2-amino-3-methyl- butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- pyrido[2,1-a]isoquinolin-2-yl ester or an isotopic variant thereof; or a pharmaceutically acceptable salt, is Form I of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt having a differential scanning calorimetric (DSC) peak temperature within 2% of 243 °C.

60. The method of claim 58 or 59, wherein the DSC peak temperature is within 1% of 243 °C.

61. The method of any one of claims 58 to 60, wherein the DSC peak temperature is within 0.5% of 243 °C.

62. The method of any one of claims 58 to 61, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 6.3°±0.2°.

63. The method of any one of claims 58 to 62, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 17.9°±0.2°.

64. The method of any one of claims 58 to 63, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising a peak at a two-theta angle of 19.7°±0.2°.

65. The method of any one of claims 58 to 64, wherein the crystalline form is stable upon exposure to about 25 °C and about 60% relative humidity.

66. The method of any one of claims 58 to 65, wherein the crystalline form has a D90 particle size of about 70 μM in length.

67. The method of any one of claims 58 to 66, wherein the crystalline form has a D10 particle size of about 10 μM in length.

68. The method of any one of claims 58 to 67, wherein the crystalline form has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt.

69. The method of any one of claims 58 to 68, wherein the crystalline form has a purity of no less than 98% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt.

70. The method of any one of claims 58 to 69, wherein the crystalline form has a purity of no less than 97% by weight of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, l-a]isoquinolin-2-yl ester tosylate salt; and has an X-ray powder diffraction (XRPD) pattern comprising peaks at two-theta angles of 6.3°±0.2°, 17.9°±0.2°, and 19.7°±0.2°.

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