VALBENAZINE FOR USE IN THE ADD-ON TREATMENT OF SCHIZOPHRENIA

BACKGROUND

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. The onset of the disease is usually in late adolescence or early adulthood. Schizophrenia presents with a heterogeneous combination of symptoms typically categorized into positive, negative, and cognitive symptoms.

While no definitive single etiology has been identified, schizophrenia has multifactorial etiological underpinnings including strong genetic contributions and prominent gene environment interactions. Schizophrenia manifests with subtle structural and functional abnormalities of various brain structures, such as the striatum, hippocampus, and prefrontal cortex. Although schizophrenia is highly heritable, as indicated by epidemiological studies, it is not a purely genetic disorder nor is it caused by a single gene. Rather, it likely results from a combination of both rare and common genetic variants, environmental risk factors, and their interactions.

Overall, patients with schizophrenia have higher mortality and morbidity rates, with a reduced expected lifespan that is nearly 20 years shorter than that of the general population.

Pharmacotherapy is the mainstay of schizophrenia management and antipsychotics are generally employed for the treatment of schizophrenia and associated symptoms; however, some patients fail to respond to antipsychotics. Additionally, antipsychotics can have a wide range of side effects and poor compliance with drug treatment is a frequent problem among schizophrenia patients. Non-compliance with antipsychotic medication can lead to relapse for patients in remission and persistent symptoms for those with existing symptoms.

BRIEF SUMMARY

In an aspect, provided herein is a method for the add-on treatment of schizophrenia, 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 has at least one symptom chosen from the following symptoms in Positive and Negative Symptom Scale (PANSS): P1 (delusions), P3 (hallucinations), P6 (suspiciousness), and G9 (unusual thought content), and further wherein the subject is also being administered at least one co-therapeutic agent for the treatment of schizophrenia.

In certain embodiments, the subject has at least one sign or symptom of schizophrenia.

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

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

In certain embodiments, the subject has a total PANSS score ≥70.

In certain embodiments, the subject has Clinical Global Impression of Severity (CGI-S) score ≥4.

In certain embodiments, the subject has a stable background antipsychotic medication dose.

In certain embodiments, the subject has a stable PANSS total score.

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

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

In certain embodiments, the mono- or combination therapy is initial therapy.

In certain embodiments, the at least one co-therapeutic agent is least one antipsychotic agent.

In certain embodiments, the antipsychotic agent is a typical antipsychotic agent.

In certain embodiments, the typical antipsychotic agent is benperidol, chlorpromazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, loxapine, molindone, pericyazine, perphenazine, pimozide, prochlorperazine, promazine, sulpiride, thiothixene, trifluoperazine, thioridazine, zuclopenthixol, or any combination thereof.

In certain embodiments, the antipsychotic agent is an atypical antipsychotic agent.

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

In certain embodiments, the subject is receiving concomitant treatment with a subtherapeutic dose of a second antipsychotic agent.

In certain embodiments, the concomitant treatment with a subtherapeutic dose of a second antipsychotic is used to treat insomnia or anxiety.

In certain embodiments, the concomitant treatment with a subtherapeutic dose of a second antipsychotic is used to treat symptoms other than refractory positive psychosis symptoms.

In certain embodiments, the subject has an inadequate response to the at least one antipsychotic agent.

In certain embodiments, the subject is on at least a second clinical use of the at least one antipsychotic agent.

In certain embodiments, the subject is also being administered risperidone and/or a risperidone equivalent.

In certain embodiments, the subject is also being administered a total daily dose of from about 4 mg to about 8 mg of risperidone and/or risperidone equivalents.

In certain embodiments, the subject is receiving background antipsychotic therapy at a total daily dose of from about 4 mg to about 8 mg of risperidone equivalents according to Table 2.

In certain embodiments, the subject has a stable antipsychotic agent dose.

In certain embodiments, the stable antipsychotic agent dose is defined as ≤25% change in risperidone equivalent total daily dose.

In certain embodiments, the subject is also being administered up to two antipsychotic agents.

In certain embodiments, the total combined antipsychotic dose is from about 4 mg to about 8 mg daily dose of risperidone equivalents according to Table 2.

In certain embodiments, the antipsychotic agent is other than clozapine.

In certain embodiments, the subject is treated with a stable regimen of antipsychotic agent(s) with no clinically meaningful change in the prescribed dose.

In certain embodiments, the no clinically meaningful change in the prescribed dose is no increase in dose or ≤25% decrease in dose for tolerability.

In certain embodiments, no dose adjustment is anticipated.

In certain embodiments, the subject is also being administered a long-acting injectable antipsychotic.

In certain embodiments, there is no dose change in the long-acting injectable antipsychotic.

In certain embodiments, the inadequate response comprises at least one baseline criterion selected from:

- Positive and Negative Symptom Scale (PANSS) total score of ≥70;
- PANSS score of ≥4 on at least one symptom selected from P1 (delusions), P3 (hallucinations), P6 (suspiciousness), and G9 (unusual thought content); Clinical Global Impression of Severity (CGI-S) score of ≥4;
- stable background antipsychotic medication dose of ≤25% change in risperidone equivalent total daily dose according to Table 2; and
  
  a stable PANSS total score of ≤15% change.

In certain embodiments, the subject has a confirmed diagnosis of schizophrenia as defined by the MINI Version 7.0.2 for Psychotic Disorders for the Psychotic Disorders for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) for a subject ≥18 years of age or K-SADS-PL for a subject 13 to 17 years of age.

In certain embodiments, the subject has a confirmed initial diagnosis of schizophrenia for at least one year.

In certain embodiments, the subject is at least 13 years of age with a body weight of at least 50 kg.

In certain embodiments, the subject is an outpatient with stable symptomatology

In certain embodiments, the subject does not have comorbid Parkinsonism and/or does not or exhibit more than a minimal level of extrapyramidal signs or symptoms as defined by a score on the modified Simpson Angus Scale (SAS; excluding #10, akathisia) >6.

In certain embodiments, the subject does not have treatment-resistant schizophrenia, as defined by at least one of the following criteria:

- a history of clozapine treatment for treatment-resistant psychosis; and/or
- a history of multiple adequate and failed antipsychotic medication trials, wherein the subject demonstrated minimal or no improvement.

In certain embodiments, the subject does not have evidence of depression as measured by a Calgary Depression Scale for Schizophrenia (CDSS) score >8.

In certain embodiments, the subject has not attempted suicide and/or does not have positive answers on item numbers 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS).

In certain embodiments, the (S)-2-amino-3-methyl-butyric acid (2R,3R,11 bR)-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.

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.

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.

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.

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.

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

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.

In certain embodiments, the methods of the present disclosure 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.

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.

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.

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

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.

In certain embodiments, the no clinically meaningful change in the prescribed dose is no increase in dose or a ≤25% decrease in dose for tolerability in the prescribed dose for ≥3 weeks.

In certain embodiments, no dose adjustment is anticipated.

In certain embodiments, the subject is also being administered a long-acting injectable antipsychotic with no dose change within 8 weeks 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.

In certain 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 has a confirmed diagnosis of schizophrenia as defined by the MINI Version 7.0.2 for Psychotic Disorders for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) for a subject ≥18 years of age or K-SADS-PL for a subject 13 to 17 years of age.

In certain 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 has at least one symptom chosen from the following symptoms in Positive and Negative Symptom Scale (PANSS): P1 (delusions), P3 (hallucinations), P6 (suspiciousness), and G9 (unusual thought content).

- a history of clozapine treatment for treatment-resistant psychosis; and/or
- a history of multiple adequate and failed antipsychotic medication trials, wherein the subject demonstrated minimal or no improvement.

In certain 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 does not have a diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar disorder; a lifetime diagnosis of obsessive-compulsive disorder; a recent occurrence of panic disorder, a depressive episode, and/or other comorbid psychiatric condition requiring clinical attention based on the MINI Version 7.0.2.

In certain 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 has not attempted suicide within one year and/or does not have positive answers on item numbers 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS).

In certain embodiments, the add-on treatment results in a change in total PANSS score from Analysis Baseline to Week 10; a change in CGI-S of illness from Analysis Baseline to Week 10, a change in Personal and Social Performance (PSP) score from Analysis Baseline to Week 10, a change in VAS scores for the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L; subjects ≥18 years old) or EQ-5D Youth (EQ-5D-Y; subjects 13 to 17 years old) from baseline to Week 10; and/or a change in Sheehan Disability Score (SDS) from baseline to Week 10.

In certain embodiments, the treatment results in a reduction in the subject's CGI-S positive symptoms, relative to the subject's score at baseline.

In certain embodiments, the treatment results in a change in EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) scores from Analysis Baseline to Week 10 and/or a change in Sheehan Disability Score (SDS) from Analysis Baseline to Week 10.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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):

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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, 1-a]isoquinolin-2-yl ester tosylate salt having a differential scanning calorimetric (DSC) peak temperature within 2% of 243° C.

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

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

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°.

In certain embodiments, the crystalline form is stable upon exposure to about 25° C. and about 60% relative humidity.

In certain embodiments, the crystalline form has a D90 particle size of about 70 μM in length.

In certain embodiments, the crystalline form has a D10 particle size of about 10 μM in length.

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, 1-a]isoquinolin-2-yl ester tosylate salt.

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, 1-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°.

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.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a schematic of the study design. The study includes a Screening Period of up to 4 weeks, a 2-week double-blind Placebo Run-in Period, an 8 week Randomized Double-Blind Treatment Period, and a 2-week Washout Period. DB=double-blind; V=visit; VBZ=valbenazine; Wk=week.

INCORPORATION BY REFERENCE

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.

DETAILED DESCRIPTION

The present disclosure is directed to methods of treating diseases or disorders relating to dopamine neurotransmission.

Dopamine neurotransmission has been implicated in the underlying pathophysiology of schizophrenia. The dopamine hypothesis of schizophrenia suggests that a dysregulated dopamine system contributes to positive, negative, and cognitive symptoms of the disease. Without wishing to be bound by theory, it is believed that subjects with inadequate response to antipsychotics may be producing dopamine at a higher level, which makes dopamine blockade in the synapse inadequate for controlling symptoms of schizophrenia.

The standard of care in schizophrenia is the use of first-generation (D2 antagonist) and second-generation (D2/HT2 antagonist) antipsychotics for reducing positive symptoms and decreasing the frequency of inpatient hospitalization. However, as many as 20% of subjects with schizophrenia experience treatment failure and are resistant to standard antipsychotics, as defined by lack of clinically important improvement in symptoms after 2 to 3 regimens of treatment with standard antipsychotic drugs. Furthermore, an additional 30% to 40% of patients improve but are residually symptomatic despite antipsychotic treatment. Certain residually symptomatic patients are offered clozapine treatment, however, because of side effects and rigor of follow up for this therapeutic agent, only a relatively small of number of these patients are maintained on the drug. Some patients are tried on two concomitant antipsychotics, yet to a low percentage success rate. Furthermore, currently available antipsychotics fail to return most patients to remission of symptoms.

The present disclosure provides compositions and methods for modulating dopaminergic transmission through inhibition of vesicular monoamine transporter 2 (VMAT2), which mediates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release, using a VMAT2 inhibitor. Monoamines include, for example, catecholamines (e.g., dopamine, norepinephrine), tryptamines (e.g., serotonin), and histamine. VMAT2 is a transporter which is present in the membrane of presynaptic vesicles in monoaminergic neurons. Their primary function appears to be packaging monoamines (e.g., dopamine) from the cytoplasm of the presynaptic neuron into vesicles for subsequent release into the synapse. Inhibition of VMAT2 results in modulated activity in associated neuronal circuits.

Valbenazine modulates dopaminergic transmission through inhibition of VMAT2, which mediates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. In one aspect, unexpectedly a VMAT2 inhibitor, such as valbenazine, acts synergistically with antipsychotics to control schizophrenia symptoms by decreasing dopamine available for release.

In certain embodiments, the adjunctive or add-on treatment of schizophrenia in a subject in need thereof with valbenazine and at least one antipsychotic reduces symptoms, prevents relapse, and/or maximizes quality of life and functioning. In other embodiments, the adjunctive or add-on treatment of schizophrenia in a subject in need thereof with valbenazine and at least one first-generation (D2 antagonist) antipsychotic and/or at least one second-generation (D2/HT2 antagonist) antipsychotic is effective for reducing positive symptoms and/or decreasing the frequency of inpatient hospitalization. In certain embodiments, adjunctive or add-on treatment of individuals with schizophrenia reduces symptoms, prevents relapse, and maximizes quality of life and functioning.

I. Definitions

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.

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.

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.

As used herein, in some embodiments, “pharmaceutically acceptable salt” refers to acid addition salts with an inorganic or an organic acid. Lists of suitable salts are found in WO 87/05297, Johnston et al., published Sep. 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.

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, “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 a patient 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.

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.

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.

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.

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.

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.

As used herein, “deutetrabenazine” may be referred to as (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxyd3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. Deutetrabenazine is a racemic mixture containing the following compounds:

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Deutetrabenazine (or d₆-tetrabenazine) as disclosed in U.S. Pat. No. 8,524,733 is administered resulting in an appropriate concentration over a specified period of time of metabolite (+)a-3-isobutyl-9, 10-d6-dimethoxy-1,3,4,6,7,11bhexahydro-2H-pyrido[2, 1-a]isoquinolin-2-ol (deuterated (+)a-HTBZ) or deuterated (+)β-HTBZ in the plasma). The d₆-tetrabenazine may be administered by a variety of methods including the formulations as disclosed in PCT Publication WO 2014/047167, the disclosure of which is incorporated herein by reference in its entirety.

As used herein, dihydrotetrabenazine may be referred to as 2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine. The compound has three chiral centers and hence can, theoretically, exist in a total of eight isomeric forms as shown below:

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The synthesis and characterization of the eight isomers is described by Sun et al. (2011) Eur. J. Med. Chem. 1841-1848.

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 valbenazine free 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.

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.

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

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.

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.

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 be ²H, as example, or any carbon can be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, and any oxygen can be ¹⁸O, 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.

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 (670.5% 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.

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.

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.

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.

As used herein, the “Mini International Neuropsychiatric Interview” or “MINI” is a brief structured diagnostic interview for the major psychiatric disorders (including schizophrenia) in the revised DSM Third Edition, DSM Fourth Edition, DSM-5, and International Statistical Classification of Diseases and Related Health Problems, Tenth Edition (ICD-10). See, e.g., Sheehan D V, Lecrubier Y, Sheehan K H, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998; 59 Suppl 20:22-33; quiz 4-57. Validation and reliability studies have been done comparing the MINI to other well-known psychiatric diagnostic interviews. The results of these studies show that the MINI has similar reliability and validity properties to these instruments but can be administered in a much shorter period of time and clinicians can use it after a brief training session. See, e.g., Sheehan D V, Lecrubier Y, Sheehan K H, et al. The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. Eur Psychiatry. 1997; 12:232-41.

The assessment of the inclusion criterion for schizophrenia will be standardized using the MINI Version 7.0.2. The MINI will also be used to evaluate the presence of comorbid psychiatric disorders to assess the appropriateness of the subject for inclusion.

As used herein, the “Kiddie Schedule for Affective Disorder and Schizophrenia for School-Age Children, Present and Lifetime Version” or “K-SADS-PL” is a semi-structured diagnostic interview in children and adolescents that combines dimensional and categorical assessment approaches to diagnose current and past episodes of psychopathology (e.g., schizophrenia and schizoaffective disorders) in children and adolescents aged 6 to 18 years using DSM-5 criteria. See, e.g., Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997; 36(7):980-88.

The “Sheehan Disability Scale” or “SDS,” as used herein, is a brief, validated measure of functional impairment in several psychiatric disorders to measure the effect of treatment on disability. See, e.g., Leon A C, Olfson M, Portera L, et al. Assessing psychiatric impairment in primary care with the Sheehan Disability Scale. Int J Psych Med. 1997 27(2):93-105. It includes 3 self-rated items designed to measure how work, social life, and family life are impaired by current psychiatric symptoms. Each item includes an 11-point analog scale that uses visual-spatial, numeric, and verbal descriptive anchors to represent the degree of disruption (0 [none at all] to 10 [extremely]). It also assesses the number of days a subject was unable to work/attend school and the number of days a subject was underproductive in the past week. The SDS will be administered as outlined in the schedule of assessments (see Table 5).

As used herein, the “Positive and Negative Symptoms Scale,” “Positive and Negative Syndrome Scale,” or “PANSS” is a reliable, well known, widely used, clinician administered, validated, 30-item scale designed to evaluate the severity of various symptoms of schizophrenia and is commonly employed in clinical studies involving antipsychotics to measure symptom reduction in patients taking antipsychotics. See, e.g., European Medicines Agency [EMA], Committee for Medicinal Products for Human Use. Guidance on the clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia. 2012; EMA/CHMP/40072/2010 Rev 1; Lehman A F, Lieberman J A, Dixon L B, et al. Treatment recommendations for patients with schizophrenia. In: Practice Guideline for the Treatment of Patients with Schizophrenia. Second edition. American Psychiatric Association; 2004: 3-35 (Part A); and Kay S R, Fiszbein A, Opler L A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13(2):261-76.

The subscales of the PANSS and the 5-factor model of the PANSS are commonly employed to assess different symptom domains of schizophrenia. The scale is divided into 3 sections with 7 items designed to evaluate positive symptoms (symptoms of the disease which manifest as the presence of traits), 7 items designed to evaluate negative symptoms (symptoms that manifest as the absence of traits), and 16 items that address general psychopathology. Each item is scored on a 7-point severity scale (1=absent; 2=minimal; 3=mild; 4=moderate; 5=moderate severe; 6=severe; 7=extreme). The scale also includes 3 supplementary items that constitute an aggression risk profile; however, these items will not be scored as they are not applicable to the study. The PANSS total score is derived from the summation of each item.

The PANSS “Positive Symptom Factor Score” or “PSFS” is broadly used in clinical studies of schizophrenia and has demonstrated both good test-retest reliability and validity for positive symptom assessment in patients. See, e.g., Lehman A F, Lieberman J A, Dixon L B, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004 February; 161(2 Suppl):1-56 and Marder S R, Davis J M, and Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived from factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997; 58:538-46.

As used herein, the “Personal and Social Performance Scale” or “PSP Scale” is a validated instrument to rate severity of illness on 4 main areas (socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior). See, e.g., Morosini et al., 2000. The subject's degree of severity in the 4 domains is rated on a 6-point scale from absent (which means no problems on this dimension), mild, manifest, marked, severe, and very severe. Out of the ratings on the four domains, a single measurement from 0 to 100% can be created. The PSP scale will be administered and scored by the investigator or other qualified site personnel.

As used herein, the “Clinical Global Impression of Severity” or “CGI-S” is a 7-point scale to assess patient's severity of illness. See, e.g., Busner J, Targum S D. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007; 4(7):28-37. CGI-S will be administered and scored by the investigator or other qualified site personnel.

As used herein, the “Abnormal Involuntary Movement Scale” or “AIMS” rating scale rates a total of 10 items with 9 items rating involuntary movement from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 comprise facial and oral movements (Items 1 to 4), extremity movements (Items 5 to 6), and trunk movements (Item 7). The AIMS dyskinesia total score for Items 1 to 7 ranges from 0 to 28; a higher score reflects increased severity. Items 8, 9 and 10 rate global judgments with Item 10 being rated based only on the subject's report of his/her awareness of abnormal movements from 0 (no awareness) to 4 (aware, severe distress). Items 11 and 12 are yes/no questions concerning problems with teeth and/or dentures. AIMS total score can range from 0 to 40. See, e.g., Guy W. Ed. ECDEU Assessment Manual of Psychopharmacology, revised, 1976. US Department of Health, Education, and Welfare. Pub. No. (ADM), 76-338. Rockville (MD): National Institute of Mental Health—Clinical Global Impression—Improvement. p. 217-22. The AIMS will be administered by the investigator or other qualified personnel.

As used herein, the “Modified Simpson Angus Scale” or “SAS” is a clinician-administered rating scale that is widely used to assess antipsychotic-induced parkinsonism in clinical practice and research settings. See, e.g., Simpson G M, Angus J W. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970; 212:11-9. The study described herein uses a modified 10-item version of the SAS (for the screening and Day 1 assessment of eligibility) in which “Leg Pendulousness” and “Head Dropping” items included in the original version have been replaced with “Head Rotation” and “Akathisia,” which has been used frequently in schizophrenia clinical trials. See, e.g., Moore T J, Furberg C D. The harms of antipsychotic drugs: evidence from key studies. Drug Saf. 2017; 40(1):3-14. Each item is rated using a 5-point scale (0-4); the modified SAS scores can range from 0 to 40.

As used herein, the “Calgary Depression Scale for Schizophrenia” or “CDSS” is used to assess symptoms of major depressive disorder in patients with schizophrenia, and specifically designed to assess comorbid depressive symptoms. See, e.g., Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl. 1993; (22):39-44. The CDSS consists of 9 items: depressed mood, hopelessness, self-deprecation, guilty ideas of reference, pathological guilt, depression worse in the morning, early wakening, suicide, and observed depression. Each item is rated using a 0 to 3 point scale (0-3); the CDSS score can range from 0 to 27. The items on the CDSS are all typical depressive symptoms and do not appear to overlap with the negative symptoms of schizophrenia. The CDSS will be conducted by the investigator or other qualified site personnel.

As used herein, the “Placebo-Control Reminder Script” or “PCRS” is a script which carefully reviews placebo response factors with research participants with the goal of reducing placebo effect through increased awareness of its impact. The PCRS script is read to each participant prior to the administration of efficacy assessments. It is followed by a discussion between the rater and participant about the key points, including understanding of double-blind clinical trials, recognition of the rater's neutral position regarding participant responses, and the importance of providing honest feedback. The PCRS mitigates expectation bias leading to increased placebo response. See, e.g., Cohen E A, Hassman H H, Ereshefsky L, et al. Placebo response mitigation with a participant focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders. Neuropsychopharmacology. 2021; 46(4):844-50.

As used herein, the “Columbia-Suicide Severity Rating Scale” or “C-SSRS” is a validated, evidence-supported scale used for suicide assessment and prospectively assesses suicidal ideation and behavior. See, e.g., The World Wide Web at cssrs.columbia.edu. The C-SSRS will be administered and scored by the investigator or qualified study site personnel.

As used herein, the “EuroQol 5 Dimensions 5 Levels” or “EQ-5D-5L” is a general, single index measure for describing and valuing health (Herdman et al., 2011). It defines health in terms of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The subject indicates his/her health state by checking the box next to the most appropriate statement. The scores for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state. Subjects also rate their overall health on a 0 to 100 hash-marked, vertical visual analogue scale (VAS). The endpoints are labeled “The best health you can imagine” and “The worst health you can imagine.”

The EQ-5D youth (EQ-5D-Y) version is a more comprehensible instrument suitable for children and adolescents. The EQ-5D-Y comprises 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-Y descriptive system comprises the following five dimensions: mobility, looking after myself, doing usual activities, having pain or discomfort and feeling worried, sad or unhappy. Each dimension has 3 levels: no problems, some problems and a lot of problems. The younger patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The EQ VAS records the subjects self-rated health on a vertical visual analogue scale where the endpoints are labeled “The best health you can imagine” and “The worst health you can imagine.” The EQ-5D-5L (subjects ≥18 years old) and the EQ-5D-Y (subjects 13 to 17 years old) will be administered by the investigator or qualified designee.

As used herein, “positive symptoms” and “positive symptoms of schizophrenia” are interchangeable and include, but are not limited to, behaviors and thoughts that are not normally present, such as psychosis, delusions, hallucinations, and disorganized speech and behavior.

As used herein, “negative symptoms” and “negative symptoms of schizophrenia” are interchangeable and include, but are not limited to, motivational syndrome comprising social withdrawal, affective flattening, anhedonia, and diminished energy. See, e.g, Fervaha G, Foussias G, Agid O, et al. Impact of primary negative symptoms on functional outcomes in schizophrenia. Eur Psychiatry. 2014 September; 29(7):449-55.

As used herein, “cognitive symptoms” and “cognitive symptoms of schizophrenia” are interchangeable and include, but are not limited to, poor information processing, impaired ability to focus on objectives, and abnormalities of working memory and learning (Kahn R S, Sommer I E, Murray R M, et al. Schizophrenia. Nat Rev Dis Primers. 2015 November; 1:15067; and van Os J and Kapur S. Schizophrenia. The Lancet. 2009 August; 374:635-45.

As used herein, “The Healthcare Utilization Questionnaire” is a questionnaire designed to evaluate whether a subject had any non-study-related health care provider interactions. The questionnaire includes 3 questions which ask subject about any hospitalizations, emergency room/urgent care visits, and outpatient visits over the past 30 days (at first use) or since the last study visit (at all subsequent uses).

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.

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.

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.

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.”

As used herein, a “product” or “pharmaceutical product” means a dosage form of an active agent plus published material, and optionally packaging.

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.

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.

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.

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 of the 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.

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).

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.

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.

As used herein, “tetrabenazine” may be referred to as 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. The compound has chiral centers at the 3- and 11b-carbon atoms and hence can, theoretically, exist in a total of four isomeric forms as shown below:

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Commercially available tetrabenazine is a racemic mixture of the RR and SS isomers. Tetrabenazine may be administered by a variety of methods including the formulations disclosed in PCT Publications WO 2010/018408, WO 2011/019956, and WO 2014/047167, the disclosure of each of which is incorporated herein by reference in its entirety.

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.

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-hexahydr 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:

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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®.

Valbenazine can be prepared according to U.S. Pat. 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. Pat. No. 10,065,952, the disclosure of which is incorporated herein by reference in its entirety.

Valbenazine Ditosylate

In another embodiment, provided herein is a crystalline form 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) or an isotopic variant thereof or solvate thereof of Formula I:

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Valbenazine Ditosylate Form I

In yet another embodiment, provided herein is a crystalline form 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) or an isotopic variant thereof or solvate thereof, wherein the crystalline form is Form I.

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°. 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°.

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 various embodiments, crystalline Form I has an endothermic differential scanning calorimetric (DSC) thermogram. 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. 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.

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.

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.

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, 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; about 33.98 and about 35.35 at approximately pH 6.8.

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%, no greater 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.

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, about 5 μM in length. In some embodiments, a sample of Form I comprises particles of about 70, about 60, about 40, about 20, 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, about 10.29 μM in length.

II. Pharmaceutical Compositions

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 a pharmaceutically acceptable salt and/or isotopic variant thereof, comprising a therapeutically effective amount of the VMAT2 inhibitor.

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 schizophrenia. In certain embodiments, the treatment is add-on or adjunctive treatment.

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.

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.

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.

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.

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.

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.

III. Methods of Use

Valbenazine can be administered for the add-on treatment of schizophrenia, according to the methods disclosed in U.S. Pat. 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. Valbenazine can be administered for the add-on treatment of schizophrenia, according to the methods disclosed in U.S. Ser. No. 17/080,343 and U.S. Pat. No. 11,04,029, the disclosure of each of which is incorporated herein by reference in its entirety. In some embodiments, valbenazine is administered for the adjunctive treatment of schizophrenia.

In an aspect, provided herein is a method for the add-on treatment of schizophrenia, 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 has at least one symptom chosen from the following symptoms in Positive and Negative Symptom Scale (PANSS): P1 (delusions), P3 (hallucinations), P6 (suspiciousness), and G9 (unusual thought content), and further wherein the subject is also being administered at least one co-therapeutic agent for the treatment of schizophrenia.

In an aspect, provided herein is a method for the adjunctive treatment of schizophrenia, 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 has at least one symptom chosen from the following symptoms in Positive and Negative Symptom Scale (PANSS): P1 (delusions), P3 (hallucinations), P6 (suspiciousness), and G9 (unusual thought content), and further wherein the subject is also being administered at least one co-therapeutic agent for the treatment of schizophrenia.

In certain embodiments, the subject has at least one sign or symptom of schizophrenia. In certain embodiments, the subject has a return or worsening of symptoms following a period of remission. In certain embodiments, the subject exhibits symptoms of a schizophrenia relapse.