New Method

Abstract

The present disclosure provides a method for treating bipolar II disorder, comprising administering to a patient in need thereof a therapeutically effective amount of lumateperone, in free form or in a pharmaceutically acceptable salt form, which may be in a deuterated form.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 871,170, filed July 7, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure relates to the use of lumateperone, in free form or in a pharma- ceutically acceptable salt form, and optionally in a deuterated form, for the treatment of bipolar II disorder. [Background technology]

[0003] Substituted heterocycle-fused gamma-carbolines, such as lumateperone, are useful in the treatment of central nervous system disorders. 2A or 5HT 2A These compounds are known to be serotonin 2A (5HT 2A ) receptors and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins. Such compounds are known to be useful primarily for the treatment of positive and negative symptoms of schizophrenia. At the dopamine D2 receptor, these compounds have dual properties, acting as both postsynaptic antagonists and presynaptic partial agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors specifically in the mesolimbic system. It is believed that this regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, together with serotonergic, glutamatergic and dopaminergic interactions, may result in antipsychotic effects on the positive, negative, affective and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder and comorbid depression, and / or as a standalone treatment for major depressive disorder. 5HT as described 2A or 5HT 2A5HT / D2 receptor ligands are also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly the behavioral disorders associated with dementia, autism, and other CNS diseases. These characteristics may improve the quality of life of schizophrenia patients and enhance their social functioning, allowing them to be more fully integrated into the family and workplace. At low doses, these compounds suppress the 5HT 2A They exhibit differential dose-dependent effects, selectively targeting the receptor and interacting gradually with D2 receptors at higher doses. As a result, at low doses, they are useful for treating sleep, aggression, and agitation. At higher doses, they can treat acute exacerbated residual schizophrenia, bipolar disorder, and mood disorders.

[0004] formula: [ka] Lumateperone, 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, is a therapeutic agent currently in clinical trials. Lumateperone selectively and simultaneously modulates serotonin, dopamine and glutamate neurotransmission. It is a potent (Ki=0.5 nM) 5HT 2A It exhibits receptor antagonism, activity as a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator consistent with in vivo presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki=32nM), high D1 receptor affinity (Ki=52nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62nM, using a variety of SERT activity assays). Lumateperone was approved by the U.S. Food and Drug Administration in 2019 for the treatment of schizophrenia and is in Phase III clinical development for the treatment of bipolar depression and agitation in dementia, including Alzheimer's disease.

[0005] Lumateperone and related compounds are disclosed in U.S. Patents 6,548,493; 7,238,690; 6,552,017; 6,713,471; U.S. Reissue Patent No. 39,680 and U.S. Reissue Patent No. 39,679 as therapeutic agents for the treatment of 5HT disorders such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache-related conditions, and social phobia. 2A They are disclosed as novel compounds useful for the treatment of disorders related to receptor modulation. PCT / US08 / 03340 and U.S. Patent No. 7,081,455 also disclose methods for preparing substituted heterocycle-fused gamma-carbolines and the use of these gamma-carbolines as serotonin agonists and antagonists useful for controlling and preventing central nervous system disorders such as addictive behaviors and sleep disorders. WO 2009 / 145900 and U.S. Pat. No. 8,598,119, as well as WO 2013 / 155506 and U.S. Patent Application Publication No. 2015 / 0080404, each of which is incorporated herein by reference, disclose the use of certain substituted heterocycle-fused gamma-carbolines for the treatment of comorbid psychosis and depressive disorders, and sleep disorders, depressive disorders and / or mood disorders in patients with psychosis or Parkinson's disease, and for the treatment or prevention of disorders associated with dementia, particularly behavioral or mood disorders such as agitation, irritability, aggressive / assaultive behavior, anger, physical or emotional outbursts, and psychosis and sleep disorders associated with dementia. WO 2009 / 114181, U.S. Pat. No. 8,648,077, and U.S. Patent Application Publication No. 2020 / 0157100 (each of which is incorporated herein by reference) disclose methods for preparing crystalline toluenesulfonic acid addition salts of certain substituted heterocyclic-fused gamma-carbolines, such as the toluenesulfonic acid addition salts (monotosylate and ditosylate) of lumateperone.

[0006] WO 2011 / 133224 and U.S. Patent No. 8,993,572 (each of which is incorporated herein by reference) disclose prodrugs / metabolites of substituted heterocyclic-fused gamma-carbolines for improved formulations, such as sustained / controlled release formulations. The present application discloses that heterocyclic-fused gamma-carbolines N-substituted with 4-fluorophenyl(4-hydroxy)butyl moieties are shown to have high selectivity for the serotonin transporter (SERT) compared to heterocyclic-fused gamma-carbolines containing 4-fluorophenylbutanone.

[0007] WO 2009 / 145900 (and U.S. Pat. No. 8,598,119) teaches that selected substituted heterocycle-fused gamma-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and are therefore selective serotonin reuptake inhibitors.

[0008] As disclosed in WO 2015 / 154025, U.S. Patent Application Publication No. 2017 / 0183350, WO 2017 / 165843, and U.S. Patent Application Publication No. 2019 / 231780, each of which is incorporated herein by reference, deuterated forms of lumateperone and related compounds have been shown to have improved metabolic stability.

[0009] According to the National Institute of Mental Health, bipolar disorder, also known as manic depression, is a brain disorder that causes abnormal changes in mood, energy, activity, and the ability to carry out daily tasks. There are four basic types of bipolar disorder; all of them involve distinct changes in mood, energy, and activity. These moods can range from periods of extremely "up" elated and energetic behavior (known as manic episodes) to periods of very sad or "down" or hopelessness (known as depressive episodes). Less severe manic periods are known as hypomanic episodes. Bipolar I Disorder - defined by a manic episode lasting at least 7 days or manic symptoms severe enough to require immediate hospital treatment. Depressive episodes usually also occur, typically lasting at least 2 weeks. Depressive episodes with mixed features (simultaneous depressive and manic symptoms) may also occur. b. Bipolar II Disorder - Defined by a pattern of depressive and hypomanic episodes rather than the full-blown manic episodes described above. c. Cyclothymic Disorder (also called cyclothymia) - defined by numerous periods of hypomanic symptoms and numerous periods of depressive symptoms lasting at least 2 years (1 year in children and adolescents), however, the symptoms do not meet the diagnostic requirements for hypomanic or depressive episodes. d. Other specified and unspecified bipolar and related disorders - defined by bipolar disorder symptoms that do not fit into the three above categories.

[0010] The etiology of bipolar disorder remains unclear, and the disorder remains resistant to treatment.Medical treatment includes mood stabilizers such as lithium or anticonvulsants (e.g., carbamazepine, lamotrigine and valproic acid).Conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are not only less effective in treating bipolar depression than major depressive disorder, but can also cause harm by causing manic episodes and rapid cycling.

[0011] Antipsychotics are generally effective for the short-term treatment of bipolar manic episodes in bipolar I disorder, but are generally ineffective for the treatment of bipolar II disorder and for maintenance therapy during depressive episodes. Furthermore, many antipsychotics exhibit significant side effects, such as acute dyskinesia and dystonic reactions, tardive dyskinesia, parkinsonism, akinesia, akathisia, and extrapyramidal symptoms, including neuroleptic malignant syndrome.

[0012] For example, the atypical antipsychotic aripiprazole has been extensively evaluated for the treatment of bipolar disorder, but a review of the clinical data concluded: "Although aripiprazole has demonstrated efficacy in acute mania and mania prophylaxis, available evidence does not support the efficacy of aripiprazole for the treatment of acute bipolar depression or for the prevention of depressive relapse." Yatham LN, "A clinical review of aripiprazole in bipolar depression and maintenance therapy of bipolar disorder." J. Affect. Disord. 2011 Jan;128 Suppl 1:S21-8. Aripiprazole is currently approved in the United States for the "acute treatment of manic and mixed episodes associated with bipolar I disorder." It is not currently approved for the treatment of bipolar II disorder.

[0013] Although there are many antipsychotics approved for the treatment of mania associated with bipolar I disorder, there are currently only four antipsychotics approved in the United States for the treatment of depression associated with bipolar I disorder, and there is currently only one antipsychotic approved in the United States for the treatment of bipolar II disorder, quetiapine (Seroquel®). However, quetiapine has been reported to be highly sedating and to cause many metabolic side effects, such as hyperglycemia, dyslipidemia, and weight gain. It has also been associated with the emergence of suicidal ideation in some patients.

[0014] Although estimates vary, approximately 30-60% of patients suffering from bipolar disorder are thought to suffer from bipolar II disorder. Despite its prevalence, bipolar II disorder is often misdiagnosed as either major depressive disorder or bipolar I disorder and, as a result, is inappropriately treated. There is a need for safer and more effective treatments for bipolar II disorder, as well as for therapies that are effective in treating both bipolar I and bipolar II disorders. Summary of the Invention

[0015] Quick Overview We have surprisingly found that lumateperone is useful in the treatment of bipolar II disorder. Clinical results suggest that lumateperone is at least as effective in this indication as existing antipsychotics in the treatment of bipolar disorder, with unexpected benefits, especially in bipolar II disorder, which is often resistant to treatment with antipsychotics. Furthermore, lumateperone exhibits a good safety profile. Clinical trials have shown that lumateperone, unlike many other antipsychotics, does not increase akathisia, agitation, or other movement disorders, does not increase suicidal ideation, and has no significant metabolic side effects.

[0016] Thus, in a first aspect, the disclosure provides a method of treating bipolar II disorder in a patient in need of such treatment, comprising administering to a patient in need of such treatment a therapeutically effective amount of lumateperone, in free base form or a pharma- ceutically acceptable salt form, which may be in a deuterated form.

[0017] Further embodiments will become apparent from the detailed description and examples which follow. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description In a Phase 3 clinical trial evaluating lumateperone as monotherapy in the treatment of major depressive episodes associated with bipolar I or bipolar II disorder, lumateperone 42 mg / day (administered orally as the tosylate 60 mg) met its primary endpoint of improvement in depression as measured by change from baseline versus placebo, Montgomery-Asberg Depression Rating Scale (MADRS) total score (p<0.001; effect size=0.56), and its key secondary endpoint of Clinical Global Impression Scale for Bipolar for Severity of Illness (CGI-BP-S) total score (p<0.001; effect size=0.46).

[0019] Additionally, patients did not exhibit manic episodes as measured by the Young Mania Rating Scale (YMRS) and specific clinical global impression of severity for mania, meaning that the drug was effective in preventing manic or hypomanic episodes and did not induce manic episodes or rapid cycling that are often associated with SSRIs in the treatment of bipolar disorder.

[0020] Unexpectedly, given the generally limited efficacy of antipsychotics in bipolar II disorder, a subgroup analysis of patients with bipolar II disorder showed that lumateperone 42 mg daily was statistically significantly superior to placebo in MADRS total score.

[0021] Lumateperone demonstrated a favorable safety profile in this study that was comparable to placebo. Unlike quetiapine, lumateperone did not appear to have significant metabolic effects such as hyperglycemia, dyslipidemia, or weight gain. There were also no reported adverse events of suicidal ideation, no suicides, and no discontinuations due to suicidal ideation. Equally important, there were no reported adverse events of extrapyramidal symptoms such as akathisia, restlessness, or other motor side effects.

[0022] Akathisia is associated with the use of most antipsychotics and antidepressants, especially in bipolar disorder. Akathisia has been associated with suicide. This highlights the clinical importance of lumateperone, as it can treat bipolar II disorder without causing akathisia and is therefore less likely to cause suicidal behavior.

[0023] In a first aspect, the present disclosure provides a method for the treatment of bipolar II disorder, comprising administering to a patient in need of said treatment a therapeutically effective amount of lumateperone, in free base form or in a pharma- ceutically acceptable salt form, which may be in a deuterated form (Method 1). In further embodiments of the first aspect, the present disclosure provides:

[0024] 1.1. Method 1, wherein lumateperone is in the form of a tosylate salt (e.g., an acid addition salt of toluenesulfonic acid, such as the monotosylate or ditosylate salt), which may be a solid crystalline salt, such as the solid crystalline salts disclosed in U.S. Patent Application Publication No. 2011 / 112105 and U.S. Patent Application Publication No. 2020 / 0157100, the contents of each of which are incorporated herein by reference in their entirety.

[0025] 1.2. Method 1, wherein lumateperone is in the free base form.

[0026] 1.3. Any of the above methods, wherein lumateperone is in a deuterated form, e.g., the deuterium:protium ratio of certain carbon-bonded hydrogen atoms is significantly higher than the natural isotope ratio, e.g., at least 2-fold, e.g., at least 10-fold higher.

[0027] 1.4. Lumateperone in free form or in the form of a pharma- ceutically acceptable salt, e.g., the tosylate salt; [ka] where D represents hydrogen positions that substantially exceed the natural deuterium incorporation (i.e., substantially greater than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. is a deuterated form selected from the group consisting of

[0028] 1.5. Any of the above methods, wherein lumateperone, in free form or in a pharma- ceutically acceptable salt form, which may be in a deuterated form, is administered in a total daily dose equivalent to 6-60 mg of the free base, e.g., 20-50 mg.

[0029] 1.6. Any of the above methods, wherein lumateperone, in free form or in a pharma- ceutically acceptable salt form, which may be in deuterated form, is administered in a total daily dose equivalent to 25-30 mg of the free base.

[0030] 1.7. Any of the above methods, wherein lumateperone, in free form or in a pharma- ceutically acceptable salt form, which may be in deuterated form, is administered in a total daily dose equivalent to 40-45 mg of the free base.

[0031] 1.8. Any of the above methods comprising once-daily administration of a unit dose for oral administration, e.g., a tablet or capsule, containing about 42 mg of lumateperone free base equivalent, in free form or in a pharma- ceutically acceptable salt form, which may be in deuterated form, in combination or association with a pharma- ceutically acceptable diluent or carrier.

[0032] 1.9. Any of the above methods comprising once-daily administration of a tablet or capsule containing about 60 mg of lumateperon tosylate, optionally in deuterated form, in combination or association with a pharma- ceutically acceptable diluent or carrier.

[0033] 1.10. Any of the above methods comprising once-daily administration of a unit dose for oral administration, e.g., a tablet or capsule, containing about 28 mg of lumateperone free base equivalent, in free form or in a pharma- ceutically acceptable salt form, which may be in deuterated form, in combination or association with a pharma- ceutically acceptable diluent or carrier.

[0034] 1.11. Any of the above methods comprising once-daily administration of a tablet or capsule containing about 40 mg of lumateperon tosylate, optionally in deuterated form, in combination or association with a pharma- ceutically acceptable diluent or carrier.

[0035] 1.12. Any of the above methods comprising once daily administration of a unit dose for subcutaneous or transmucosal administration, such as a sublingual or buccal orally disintegrating tablet or film, comprising lumateperone in free form or in a pharma- ceutically acceptable salt form, optionally in a deuterated form, in an amount equivalent to 10-60 mg of the free base, and a pharma- ceutically acceptable diluent or carrier.

[0036] 1.13. Any of the above methods comprising administration of a long-acting injectable form of lumateperone in free form or in a pharma- ceutically acceptable salt form, which may be in a deuterated form.

[0037] 1.14. Any of the above methods, wherein the patient has been diagnosed with bipolar II disorder.

[0038] 1.15. Any of the above methods, wherein the condition to be treated is depression in bipolar II disorder, or a depressive episode associated with bipolar II disorder (eg, a major depressive episode).

[0039] 1.16. Any of the above methods wherein the condition to be treated includes mixed affective episodes in bipolar II disorder.

[0040] 1.17. Any of the above methods, wherein the condition to be treated comprises a hypomanic episode.

[0041] 1.18. Any of the above methods, wherein treatment suppresses mania or hypomania.

[0042] 1.19. Any of the above methods, wherein treatment does not induce manic or hypomanic episodes or rapid cycling.

[0043] 1.20. Any of the above methods, wherein during the course of treatment, the patient does not exhibit episodes of mania or hypomania as measured by the Young Mania Rating Scale (YMRS).

[0044] 1.21. Any of the above methods, wherein during the course of treatment, the patient exhibits improvement in depressive symptoms as measured, for example, using one or more of the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), Zung Self-Rating Depression Scale, Wechsler Depression Rating Scale, Raskin Depression Rating Scale, Inventory of Depressive Symptomatology (IDS), or Quick Inventory of Depressive Symptomatology (QIDS).

[0045] 1.22. Any of the above methods, wherein the patient demonstrates improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total score during the course of treatment (e.g., improvement within 8 days of initiating treatment).

[0046] 1.23. Any of the above methods, wherein after treatment, the patient shows improvement in Clinical Global Impression of Bipolar Disorder Severity Scale (CGI-BP-S) (e.g., improvement within 8 days of initiating treatment).

[0047] 1.24. Any of the above methods, wherein during the course of treatment, the patient demonstrates improvement in the Clinical Global Impression Scale for Bipolar Depression for Severity of Illness (CGI-BP-Depression-S) (e.g., improvement within 8 days of initiating treatment).

[0048] 1.25. Any of the above methods, wherein during the course of treatment the patient does not demonstrate an increase in the Clinical Global Impression Scale for Bipolar Mania for Severity of Illness (CGI-BP-Impression-S).

[0049] 1.26. Any of the above methods, wherein during the course of treatment, the patient shows improvement in overall mental health (e.g., improvement within 8 days of starting treatment), as measured, for example, using the Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I).

[0050] 1.27. Any of the above methods, wherein the treatment does not cause metabolic side effects, eg, does not cause one or more of hyperglycemia, dyslipidemia or weight gain.

[0051] 1.28. Any of the above methods, wherein the treatment does not induce suicidal ideation or suicidal thoughts.

[0052] 1.29. Any of the above methods, wherein the treatment does not induce one or more of extrapyramidal symptoms, such as akathisia, akinesia, restlessness, acute dyskinesia, dystonic reactions, tardive dyskinesia, parkinsonian symptoms, or neuroleptic malignant syndrome.

[0053] 1.30. Any of the above methods, wherein the treatment does not induce akathisia.

[0054] 1.31. Any of the above methods, wherein lumateperone, in free base form or a pharma- ceutically acceptable salt form, optionally in deuterated form, is administered as monotherapy for the treatment of bipolar II disorder.

[0055] 1.32. Any of the above methods, wherein the patient is concurrently receiving a mood stabilizer selected from lithium, carbamazepine, oxcarbazepine, lamotrigine and valproic acid (including divalproex (also known as valproic acid semisodium), sodium valproate, and other free, salt or complex forms of valproic acid).

[0056] 1.33. Any of the above methods, wherein the patient is concurrently receiving lithium or valproate.

[0057] 1.34. Any of the above methods, wherein the patient is under 18 years of age.

[0058] 1.35. Any of the above methods, wherein the patient is an adult, e.g., 18 years of age or older, e.g., 18 to 75 years of age, inclusive.

[0059] 1.36. Any of the above methods, wherein the patient is elderly, e.g., 65 years or older, e.g., 75 years or older.

[0060] 1.37. Any of the above methods, wherein lumateperone, free or salt form, is used to treat depression in bipolar I disorder and bipolar II disorder.

[0061] 1.38. Any of the above methods, wherein the treatment duration is 6 weeks or less.

[0062] 1.39. Any of the above methods, wherein the treatment is a maintenance treatment.

[0063] 1.40. Any of the above methods wherein the treatment duration is 6 weeks or longer.

[0064] 1.41. Any of the above methods, wherein the patient has previously been treated with an SSRI (e.g., the treatment was ineffective and / or was discontinued due to side effects, etc.).

[0065] 1.42. Method 1.41, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0066] 1.43. Any of the above methods, wherein the patient has previously been treated with an antipsychotic, such as an atypical antipsychotic (e.g., the treatment was ineffective and / or was discontinued due to side effects, etc.).

[0067] 1.44. Antipsychotics may cause haloperidol Ru, Method 1.43, selected from aripiprazole, quetiapine, olanzapine, risperidone, lurasidone, paliperidone, iloperidone, ziprasidone, brexipiprazole, asenapine, clozapine, and zotepine.

[0068] In another aspect, the disclosure provides lumateperone, in free form or a pharma- ceutically acceptable salt form, optionally in deuterated form, for use in the treatment of bipolar II disorder, e.g., for use in any of Methods 1 et seq.

[0069] In another aspect, the disclosure provides for the use of lumateperone, in free form or a pharma- ceutically acceptable salt form, optionally in deuterated form, in the manufacture of a medicament for the treatment of bipolar II disorder, such as a medicament for use in any of Methods 1 or more.

[0070] The terms "treatment" and "treating" should be appropriately understood to encompass prevention and treatment or amelioration of disease and / or treatment of the cause of disease. In certain embodiments, the terms "treatment" and "treating" refer to the prevention or amelioration of symptoms of disease.

[0071] As used herein, "patient" means a human patient, unless otherwise specified.

[0072] Pharmaceutically acceptable salts of lumateperone include pharma- ceutically acceptable acid addition salts, such as the toluenesulfonic acid addition salt (tosylate). Tosylate salts of lumateperone include the mono-tosylate and di-tosylate salts. Unless otherwise specified, the term "lumateperone tosylate" refers to the mono-tosylate salt. Lumateperone tosylate is available as Caplyta®. TM ). When dosages or amounts of a salt are given by weight, e.g., milligrams per day or milligrams per unit dose, unless otherwise specified, the dosage of the salt is given as the weight of the corresponding free base.

[0073] The term "concurrently" when referring to therapeutic use means administration of two or more components to a patient as part of a regimen for the treatment of a disease or disorder, regardless of whether the two or more active agents are administered at the same or different times, or by the same or different routes of administration. Concurrent administration of two or more active ingredients can occur at different times on the same day, or on different days, or with different frequencies.

[0074] Dosages used in the practice of the present disclosure will, of course, vary depending upon, for example, the particular disease or condition to be treated, the particular active compound used, the mode of administration, and the desired therapy, etc. Lumateperone, in free form or in a pharma- ceutically acceptable salt form, which may be in a deuterated form, can be administered by any suitable route, including orally, parenterally, transdermally, or transmucosally, for example, in the form of a tablet, capsule, subcutaneous injection, long-acting injection (depot), or intraoral rapidly disintegrating tablet or film for sublingual or buccal administration.

[0075] In some embodiments, lumateperone is provided as a tablet or capsule for oral administration comprising lumateperone tosylate in combination with a pharma- ceutically acceptable diluent or carrier.

[0076] In some embodiments, lumateperone is provided as a rapidly disintegrating tablet or film for sublingual or buccal administration comprising lumateperone tosylate in combination with a pharma- ceutically acceptable diluent or carrier.

[0077] In some embodiments, lumateperone, either in free form or in a pharma- ceutically acceptable salt form, which may be in a deuterated form, is administered as a depot formulation, e.g., by dispersing, dissolving, suspending, or encapsulating the compound in a polymer matrix as described herein, such that the compound is released continuously as the polymer degrades over time. Release of lumateperone from the polymer matrix provides, for example, controlled and / or delayed and / or sustained release from the pharmaceutical depot composition to the subject (e.g., a warm-blooded animal such as a human) to which the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers lumateperone to the subject over an extended period of time, e.g., one week to three months, at a concentration effective to treat a particular disease or condition.

[0078] Polymers useful for the polymer matrix in the compositions of the invention (e.g., depot compositions of the invention) include polyesters of hydroxy fatty acids and derivatives thereof, or other agents, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polyβ-hydroxybutyric acid, ε-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers), polymers of alkyl α-cyanoacrylates (e.g., poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonates, polyamino acids (e.g., polyγ-L-alanine, poly-γ-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), hyaluronic acid esters, and the like, one or more of which may be used.

[0079] When the polymers are copolymers, they may be random, block and / or graft copolymers. When the above-mentioned α-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-isomers, L-isomers and / or DL-isomers may be used. In particular, α-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-α-cyanoacrylic acid esters and the like may be used, and lactic acid-glycolic acid copolymers (also called poly(lactide-α-glycolide) or poly(lactic acid-co-glycolic acid), hereinafter referred to as PLGA) are preferred. Thus, in one embodiment, the polymer useful for the polymer matrix is ​​PLGA. As used herein, the term PLGA includes polymers of lactic acid (also called polylactide, poly(lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer such as PLGA 50:50, PLGA 85:15, PLGA 90:10.

[0080] In one such embodiment, the polymeric matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not induce significant inflammation in body tissues. The matrix material must be biodegradable, that is, the polymeric material must be broken down by bodily processes into products that are easily disposable by the body and must not accumulate within the body. The products of biodegradation must also be biocompatible with the body in that the polymeric matrix is ​​biocompatible with the body. Particularly useful examples of polymeric matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearate. One suitable polymer for use in the practice of the invention is dl(polylactide-co-glycolide). In one embodiment, the molar ratio of lactide to glycolide in such copolymers ranges from about 75:25 to 50:50.

[0081] Useful PLGA polymers may have a weight average molecular weight of about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights may be used. For a diffusion mechanism of drug release, the polymer must remain intact until all of the drug has been released from the polymer matrix and then degraded. Drugs may also be released from the polymer matrix as the polymeric excipient bioerodes.

[0082] PLGA can be prepared by conventional methods or can be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization with an appropriate catalyst (see EP 0058481 B2; Effect of polymerization variables on PLGA properties: molecular weight, composition, chain structure).

[0083] PLGA is believed to be biodegradable by degradation of the entire solid polymer composition through the breakdown of hydrolyzable and enzymatically cleavable ester bonds under biological conditions (e.g., in the presence of moisture and biological enzymes found in the tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic normal metabolic products that can further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade in the body of a warm-blooded animal, such as a human, by hydrolysis of its ester groups in the presence of water to produce lactic acid and glycolic acid to create an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as a human under normal physiological conditions, and therefore are well tolerated and produce minimal systemic toxicity.

[0084] For the avoidance of doubt, disclosure of a numerical range, e.g., an amount "up to X," is intended to include the upper numerical limit X. Thus, disclosure of "up to 60 mg" is intended to include 60 mg.

[0085] All references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between a definition in this disclosure and a definition in a reference, this disclosure controls.

[0086] The present disclosure is further described in the following examples, which are meant to be illustrative and not limiting. EXAMPLES

[0087] Example 1: Clinical Trial in Patients with Bipolar I and Bipolar II Disorder A multicenter, multinational, randomized, double-blind, fixed-dose, placebo-controlled clinical trial will be conducted substantially according to the following protocol.

[0088] Patients will be recruited according to the following criteria: - Main study inclusion criteria: Male or female subjects of any race, age 18-75 years, including borderline, with a clinical diagnosis of bipolar I or bipolar II disorder, currently experiencing a major depressive episode, and able to provide written informed consent. - Main study exclusion criteria: pregnant or lactating female subjects, and subjects deemed medically unfit to participate in the study.

[0089] A total of 381 patients recruited according to the above criteria will be randomized 1:1 into two study arms: (i) lumateperone 42 mg (administered orally as lumateperone tosylate 60 mg) and (ii) placebo. In the lumateperone group, lumateperone (lumateperone tosylate 60 mg) will be administered orally once daily, nightly, for 6 weeks. In the placebo group, placebo will be administered once daily, nightly, for 6 weeks. Patients will not be receiving other medications for the treatment of bipolar disorder. The study is quadruple masked (i.e., participants, healthcare professionals, investigators, and outcome assessors).

[0090] The total study duration will be approximately 10 weeks, including a maximum 2-week screening period (washout of prohibited drugs), a 6-week double-blind treatment period, and a 2-week safety follow-up period.

[0091] The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS) [time frame: day 43]. Secondary outcome measures were the Clinical Global Impression Scale, Bipolar version (CGI-BP) [time frame: day 43] and the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) [time frame: day 43].

[0092] Additional objectives of this study are to determine the safety and tolerability of lumateperone versus placebo, as measured by: a. Incidence of adverse events (AEs) b. Young Mania Rating Scale (YMRS) c. Columbia-Suicide Severity Rating Scale (C-SSRS) d. Abnormal Involuntary Movement Scale (AIMS) e. Barnes Akathisia Rating Scale (BARS) f. Simpson-Angus Scale (SAS) g. Clinical Laboratory Evaluation h. Electrocardiogram (ECG) i. Vital signs measurement j. Physical and neurological examination.

[0093] The disposition of the drug in patients is as follows: [Table 1]

[0094] Changes from baseline to day 43 in MADRS total score were: [Table 2]

[0095] Changes from baseline to day 43 in CGI-BP-S total score were: [Table 3]

[0096] Thus, lumateperone 42 mg was superior to placebo as shown by statistically significant improvements in the primary and key secondary measures in the study, MADRS total score and CGI-BP-S. The improvements seen in this study with lumateperone 42 mg are considered clinically meaningful.

[0097] The safety profile of lumateperone was similar to placebo. A summary of treatment-emergent adverse events (TEAEs) is as follows: [Table 4]

[0098] Lumateperone 42 mg was generally safe and well tolerated. The most commonly reported adverse events observed in rates greater than 5% higher than placebo were headache, somnolence, and nausea. Importantly, rates of akathisia and extrapyramidal symptoms were less than 1%, similar to placebo.

[0099] In this study, lumateperone 42 mg once daily met the primary endpoint with a statistically significantly greater improvement than placebo at week 6 (study endpoint) as measured by change from baseline in MADRS total score. In the intention-to-treat (ITT) study population, the least squares (LS) mean reduction from baseline was 16.7 points for lumateperone 42 mg compared with 12.1 points for placebo (LS mean difference = 4.6 points, effect size = 0.56, p < 0.001). Furthermore, lumateperone 42 mg demonstrated a statistically significant separation from placebo as early as week 1 that was maintained at all time points throughout the study.

[0100] Lumateperone 42 mg also achieved the key secondary endpoints of statistically significant improvement in CGI-BP-S total score (p<0.001; effect size=0.46) and the CGI component assessing depression specifically (CGI-S Depression score; p<0.001; effect size=0.5).

[0101] These results were supported by statistically significant benefits on responder and remission rates. The study has been published in the journal Neuropsychiatry and Neurology, and has demonstrated the clinical relevance of the primary outcomes. In a subgroup analysis of patients with type 2 diabetes, lumateperone 42 mg was associated with a significant improvement in MADRS total score. was statistically significantly superior to placebo in both groups. The present application also includes the following aspects. [Aspect 1] A method for treating bipolar II disorder, comprising administering to a patient in need of such treatment either in free form or in a pharmaceutical A therapeutically effective amount of lumateperone in the form of a physiologically acceptable salt, which may be in a deuterated form. The method of claim 1, further comprising administering [Aspect 2] Lumateperone is available as a toluenesulfonic acid addition salt (e.g., the monotosylate or ditosylate salt) 2. The method of embodiment 1, wherein the compound is in the form of [Aspect 3] The method of embodiment 2, wherein the salt is a solid crystalline salt. [Aspect 4] The method of any one of aspects 1-3, wherein the lumateperone is in deuterated form. [Aspect 5] Lumate, in free form or in pharma- ceutically acceptable salt form, may be in deuterated form. Any of aspects 1 to 4, wherein peron is administered at a total daily dose equivalent to 6 to 60 mg of the free base. The method according to any one of the preceding claims. [Aspect 6] Approximately 60 mg of lumateperon tosylate is combined with a pharma- ceutically acceptable diluent or carrier. any of the above, including once-daily administration of a tablet or capsule containing The method according to any one of the above aspects. [Aspect 7] The condition being treated is depression in bipolar II disorder or Any of the above conditions that are associated with a depressive episode (e.g., a major depressive episode) The method according to the above. [Aspect 8] During the course of treatment, patients scored on the Montgomery-Asberg Depression Rating Scale (MADRS). and / or Clinical Global Impression of Bipolar Disorder Severity. The above shows improvement in the scale (CGI-BP-S) (e.g., improvement within 8 days after starting treatment). The method according to any one of the above aspects. [Aspect 9] Treatment may include hyperglycemia, dyslipidemia, weight gain, suicidal ideation, or One of the extrapyramidal symptoms, including suicidal thoughts or akathisia 4. The method according to any of the above aspects, wherein the method does not cause the above. [Aspect 10] The method according to any of the above aspects, wherein the patient is concurrently receiving a mood stabilizer. . [Aspect 11] If the patient had previously been treated with an SSRI (e.g., the treatment was ineffective), and / or discontinued due to side effects, etc.), method. [Aspect 12] Patients were previously treated with antipsychotics, such as atypical antipsychotics (e.g. The treatment was not effective and / or was discontinued due to side effects, etc. The method according to any one of the preceding aspects. [Aspect 13] Antipsychotics include haloperidol Ru, Aripiprazole, Quetiapine, Olanzapine, Risperidone, lurasidone, paliperidone, iloperidone, ziprasidone, brexpip selected from brexipiprazole, asenapine, clozapine and zotepine; The method according to embodiment 12. [Aspect 14] In a free form or in a pharma- ceutically acceptable form for use in the method according to any of the above aspects Lumateperone in salt form, optionally in deuterated form.

Claims

1. A pharmaceutical composition for the treatment of bipolar II disorder, comprising a therapeutically effective amount of lumateperone in toluenesulfonic acid addition salt form, optionally in deuterated form, wherein the pharmaceutical composition comprises lumateperone in the toluenesulfonic acid addition salt form in a total daily dose equivalent to 6-60 mg of the free base; The pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein the toluenesulfonic acid addition salt is a monotosylate salt.

3. 3. The pharmaceutical composition of claim 2, wherein the salt is a solid crystalline salt.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein lumateperone is in deuterated form.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising lumateperone in the form of a toluenesulfonic acid addition salt, optionally in a deuterated form, in a total daily dose equivalent to 25 to 50 mg of the free base.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, formulated for once-daily administration as a tablet or capsule containing about 60 mg of lumateperon tosylate in combination or association with a pharma- ceutical acceptable diluent or carrier.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the condition to be treated is depression in bipolar II disorder, or a depressive episode (e.g. a major depressive episode) associated with bipolar II disorder.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein during the course of treatment, the patient shows improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score and / or shows improvement in the Clinical Global Impression of Bipolar Disorder Severity Scale (CGI-BP-S).

9. The pharmaceutical composition of claim 8, wherein improvement in the MADRS total score is observed within 8 days after initiating treatment.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the treatment does not cause one or more of the following extrapyramidal symptoms including hyperglycemia, dyslipidemia, weight gain, suicidal ideation or thoughts, or akathisia.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the patient is concurrently receiving a mood stabilizer.

12. 12. The pharmaceutical composition of claim 11, wherein the patient is concurrently receiving lithium, carbamazepine, oxcarbazepine, lamotrigine, valproic acid or a salt or complex of valproic acid.

13. 12. The pharmaceutical composition of claim 11, wherein the patient is concurrently receiving lithium, valproic acid, or a salt or complex of valproic acid.

14. 14. The pharmaceutical composition of claim 13, wherein the salt or complex of valproic acid is valproic acid semisodium or sodium valproate.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the patient has previously been treated with an SSRI (e.g., the treatment was ineffective and / or was discontinued due to side effects, etc.).

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the patient has previously been treated with an antipsychotic, such as an atypical antipsychotic (e.g. the treatment was ineffective and / or was discontinued due to side effects, etc.).

17. 17. The pharmaceutical composition of claim 16, wherein the antipsychotic is selected from haloperidol, aripiprazole, quetiapine, olanzapine, risperidone, lurasidone, paliperidone, iloperidone, ziprasidone, brexipiprazole, asenapine, clozapine, and zotepine.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the condition to be treated is a depressive episode associated with bipolar II disorder.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the treatment period is 6 weeks or longer.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the patient does not exhibit manic episodes as measured by the Young Mania Rating Scale (YMRS).

21. 1. Use of lumateperone in toluenesulfonic acid addition salt form, optionally in deuterated form, in the manufacture of a medicament for the treatment of bipolar II disorder, comprising wherein the medicament comprises lumateperone in the toluenesulfonic acid addition salt form in a total daily dose equivalent to 6-60 mg of the free base; The use of lumateperone.

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