Methods of schizophrenia treatment

Abstract

To provide a method for the treatment of schizophrenia in adults.SOLUTION: A method for the treatment of schizophrenia in adult patients, the method comprising administering, in a capsule dosage form, a daily oral dose of 42 mg of lumateperone or 60 mg of lumateperone tosylate to a patient in need thereof, where the daily oral dose may be taken with food.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This is an international application claiming priority to and the benefit of U.S. Provisional Application No. 62 / 950,828, filed December 19, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present disclosure relates to the treatment of schizophrenia in adults comprising the administration of a pharmaceutical capsule containing 42 mg of lumateperone (60 mg of lumateperone tosylate). [Background technology]

[0003] Lumateperone, a substituted heterocyclic fused γ-carboline with the chemical name 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one, binds to serotonin receptors (5-HT 2A It is known to be a ligand for dopamine receptors (D1 and / or D2), dopamine receptors, and the serotonin transporter (SERT). It has been disclosed to be useful in the treatment of various central nervous system disorders. It exists as a stable crystalline monotosylate salt, lumateperone tosylate [4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one·4-methylbenzenesulfonate].

[0004] Lumateperone inhibits serotonin-2A (5-HT 2A) receptor antagonists and / or as modulators of dopamine receptor signaling at the level of key intracellular phosphoproteins. This compound is primarily known to be useful for treating the positive and negative symptoms of schizophrenia. This compound has been shown to have dual properties at the dopamine D2 receptor, acting as both a postsynaptic antagonist and a presynaptic partial agonist of the D2 receptor. It also stimulates the phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors specifically in the mesolimbic system. This regional selectivity in brain regions thought to mediate antipsychotic efficacy, along with serotonergic, glutamatergic, and dopaminergic interactions, is thought to result in antipsychotic efficacy against the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition, resulting in antidepressant activity for the treatment of schizoaffective disorder and co-morbid depression. Lumateperone, at low doses, inhibits 5-HT 2A It selectively targets D2 receptors, while at high doses it interacts gradually with D2 receptors, showing differential dose-dependent effects.As a result, at low doses it is effective in treating sleep, aggression and agitation.At high doses it can treat acute exacerbation and residual schizophrenia, bipolar disorder and mood disorders.

[0005] Lumateperone and related compounds are disclosed in U.S. Patent Nos. 5,629,999; 5,7 ... and 5,729,999. 5-HT1 inhibitors for the treatment of anxiety, depression, sleep disorders, and schizophrenia. 2ALumateperone has been disclosed as a novel compound useful for treating disorders associated with receptor modulation. Patent Document 7 (incorporated herein by reference) discloses the use of lumateperone for the treatment of a combination of psychosis and depressive disorder, as well as sleep disorders, depressive disorders, and / or mood disorders in psychotic patients. Patent Document 8 (incorporated herein by reference) discloses a method for preparing a crystalline toluenesulfonic acid addition salt of lumateperone. Patent Document 9 discloses that lumateperone may be particularly effective in treating acute depression and acute anxiety due to its rapid onset of action compared to existing antidepressants. This is thought to be due to signal transduction via a neurotransmitter system separate from the conventional monoamine signaling system. Lumateperone, coupled with activation of the mTOR (e.g., mTORC1) signaling pathway, results in a dopamine D1 receptor-dependent increase in NMDA and AMPA currents. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 6,548,493 [Patent Document 2] U.S. Patent No. 7,238,690 [Patent Document 3] U.S. Patent No. 6,552,017 [Patent Document 4] U.S. Patent No. 6,713,471 [Patent Document 5] U.S. Patent Reissue No. 39680 [Patent Document 6] U.S. Reissue Patent No. 39679 [Patent Document 7] U.S. Patent No. 8,598,119 [Patent Document 8] U.S. Patent No. 8,648,077 [Patent Document 9] International Publication No. 2019 / 178484 Summary of the Invention

[0007] The present disclosure provides a method for treating schizophrenia in adults, comprising administering a pharmaceutical capsule containing 42 mg of lumateperone (60 mg of lumateperone tosylate) to a patient in need of such treatment. In some embodiments, the capsule is administered with food. In some embodiments, the patient does not suffer from moderate or severe hepatic impairment, or does not concomitantly take a CYP3A4 inducer or CYP3A4 inhibitor, or is not 65 years of age or older, or does not have dementia-related psychosis. In some embodiments, the patient has a history of one or more of dementia-related psychosis, seizures, orthostatic hypertension or syncope, cerebrovascular disease (e.g., stroke), cardiovascular disease (e.g., myocardial infarction or heart failure), tardive dyskinesia, hyperglycemia or diabetes mellitus, dyslipidemia, and difficulty maintaining weight. [Brief explanation of the drawings]

[0008] [Figure 1] Influence of intrinsic factors on lumateperone pharmacokinetics. The graph shows the change (fold change and 90% confidence interval) in Cmax (maximum plasma concentration) and AUCt (area under the plasma concentration versus time curve) in patients with hepatic or renal impairment.

[0009] [Figure 2] Effect of other drugs on lumateperone pharmacokinetics. This graph shows the change (fold change and 90% confidence interval) in Cmax (maximum plasma concentration) and AUCt (area under the plasma concentration versus time curve) in patients receiving concomitant treatment with itraconazole, diltiazem, or rifampin.

[0010] [Figure 3] Change from baseline over time (weeks) in PANSS total scores for patients with schizophrenia in Study 2. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description Lumateperone (administered as lumateperone tosylate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. Currently, only the lumateperone tosylate form (lumateperone monotosylate) has regulatory approval in the United States. The recommended dose of this drug is 42 mg of lumateperone administered orally once daily, equivalent to 60 mg of lumateperone tosylate. Lumateperone is administered orally as a capsule, preferably with food. Unlike other atypical antipsychotics, no dose titration is required.

[0012] Accordingly, the present disclosure provides a method of treating schizophrenia in an adult patient (Method 1), comprising administering to the patient in need thereof a daily oral dose of 42 mg of lumateperone (e.g., in free form or in a pharmaceutically acceptable salt form) or 60 mg of lumateperone tosylate in a capsule dosage form. In a further embodiment of Method 1, the present disclosure provides:

[0013] 1.1. Method 1, wherein the oral daily dose of lumateperone 42 mg (lumateperone tosylate 60 mg) is provided as one capsule, and the oral daily dose may be taken with food.

[0014] 1.2. Method 1.1, wherein the capsule has a blue cap and an opaque white body.

[0015] 1.3. Method 1.1 or 1.2, wherein the capsules are provided in a blister pack or box (e.g., a box of 30).

[0016] 1.4. Any of methods 1.1-1.3, wherein the capsule further comprises croscarmellose sodium, gelatin, magnesium stearate, mannitol, talc, and coloring agents (e.g., titanium dioxide, FD&C Blue #1, and / or FD&C Red #3).

[0017] 1.5. Method 1.4, wherein the capsule is composed of lumateperon tosylate, croscarmellose sodium, gelatin, magnesium stearate, mannitol, talc, and coloring agents (e.g., titanium dioxide, FD&C Blue #1, and / or FD&C Red #3).

[0018] 1.6. Method 1 or any of 1.1-1.5, where the patient is under 65 years of age and / or does not have or have a history of dementia-related psychosis.

[0019] 1.7. Method 1 or any of 1.1-1.5, where the patient is at least 65 years of age and / or has dementia-related psychosis or a history of dementia-related psychosis.

[0020] 1.8. Method 1.7, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the onset or risk of onset of dementia-related psychosis.

[0021] 1.9. Method 1 or any of 1.1-1.8, where the patient is not receiving concomitant treatment with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin, aprepitant, armodafinil, pioglitazone, prednisone), moderate or strong CYP3A4 inhibitors (e.g., moderate: amprenavir, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole, fluvoxamine, verapamil; strong: clarithromycin, grapefruit juice, itraconazole, voriconazole, nefazodone, ritonavir, nelfinavir), and / or UGT inhibitors (e.g., valproic acid, probenecid).

[0022] 1.10. Method 1 or any of 1.1-1.8, where the patient is receiving concomitant treatment with a CYP3A4 inducer, a moderate or strong CYP3A4 inhibitor, and / or a UGT inhibitor.

[0023] 1.11. Method 1.10, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the need to receive concomitant treatment with a CYP3A4 inducer, a moderate or strong CYP3A4 inhibitor, and / or a UGT inhibitor, or due to side effects resulting from concomitant treatment with a CYP3A4 inducer, a moderate or strong CYP3A4 inhibitor, and / or a UGT inhibitor.

[0024] 1.12. The patient does not have moderate or severe hepatic impairment (e.g., Child-Pugh classification B or C) or the patient has mild hepatic impairment (e.g., Child-Pugh classification A), either Method 1 or 1.1–1.11.

[0025] 1.13. Patients have moderate or severe hepatic impairment (e.g., Child-Pugh classification B or C), either Method 1 or 1.1–1.11.

[0026] 1.14. Method 1.13, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of moderate or severe liver damage.

[0027] 1.15. Method 1 or any of 1.1 to 1.14, where the patient does not have or is not at risk of developing tardive dyskinesia.

[0028] 1.16. Method 1 or any of 1.1 to 1.14, where the patient has or is at risk of developing tardive dyskinesia.

[0029] 1.17. Method 1.16, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of tardive dyskinesia.

[0030] 1.18. The patient does not have or is not at risk for developing hyperglycemia or diabetes mellitus (e.g., the patient has no history of hyperglycemia or diabetes mellitus), Method 1, or any of 1.1-1.17.

[0031] 1.19. The patient has or is at risk for developing hyperglycemia or diabetes mellitus (e.g., the patient has a history of hyperglycemia or diabetes mellitus), Method 1, or any of 1.1-1.17.

[0032] 1.20. Method 1.19, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of hyperglycemia or diabetes mellitus.

[0033] 1.21. The patient does not have or is not at risk for developing dyslipidemia (e.g., the patient has no history of dyslipidemia), Method 1, or any of 1.1 to 1.20.

[0034] 1.22. The patient has or is at risk for developing dyslipidemia (e.g., the patient has a history of dyslipidemia), Method 1 or any of 1.1-1.20.

[0035] 1.23. Method 1.22, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of dyslipidemia.

[0036] 1.24. The patient is not weight gain or at risk of developing weight gain (e.g., the patient has no history of weight management difficulties), Method 1 or any of 1.1-1.23.

[0037] 1.25. The patient is weight gain or at risk of developing weight gain (e.g., the patient has a history of weight management difficulties), Method 1 or any of 1.1-1.23.

[0038] 1.26. Method 1.25, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the onset or risk of onset of weight gain.

[0039] 1.27. Method 1, or any of 1.1-1.26, wherein the patient does not have or is not at risk for developing leukopenia, neutropenia, and / or agranulocytosis (e.g., as determined by a CBC test including WBC and ANC).

[0040] 1.28. Method 1, or any of 1.1-1.26, wherein the patient has or is at risk of developing leukopenia, neutropenia, and / or agranulocytosis (e.g., as determined by a CBC test including WBC and ANC).

[0041] 1.29. Method 1.28, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of leukopenia, neutropenia, and / or agranulocytosis (e.g., as determined by a CBC test including WBC and ANC).

[0042] 1.30. The patient does not have or is not at risk for orthostatic hypertension or syncope (e.g., the patient has no history of orthostatic hypertension or syncope), Method 1, or any of 1.1-1.29.

[0043] 1.31. The patient has or is at risk for developing orthostatic hypertension or syncope (e.g., the patient has a history of orthostatic hypertension or syncope), Method 1 or any of 1.1-1.29.

[0044] 1.32. Method 1.31, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of orthostatic hypertension or syncope.

[0045] 1.33. The patient does not have or is not at risk for developing seizures (e.g., the patient has no history of seizures or a lowered seizure threshold), Method 1, or any of 1.1-1.32.

[0046] 1.34. The patient has or is at risk for developing seizures (e.g., the patient has a history of seizures or a lowered seizure threshold), Method 1 or any of 1.1-1.32.

[0047] 1.35. Method 1.34, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the onset or risk of onset of seizures or a lowered seizure threshold.

[0048] 1.36. The patient does not have or is not at risk for developing cognitive or motor dysfunction (e.g., the patient has no history of cognitive or motor dysfunction), Method 1, or any of 1.1-1.35.

[0049] 1.37. The patient has or is at risk for developing cognitive or motor impairment (e.g., the patient has a history of cognitive or motor impairment), Method 1 or any of 1.1-1.35.

[0050] 1.38. Method 1.37, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of cognitive or motor dysfunction.

[0051] 1.39. The patient does not have or is not at risk for developing thermoregulation disorders (e.g., the patient has no history of thermoregulation disorders, or the patient is not concomitantly engaged in strenuous exercise, or exposed to extreme heat or dehydration, or taking concomitant anticholinergic medications), Method 1, or any of 1.1-1.38.

[0052] 1.40. The patient has or is at risk for developing thermoregulation dysfunction (e.g., the patient has a history of thermoregulation dysfunction, or the patient has concomitantly engaged in strenuous exercise, or been exposed to extreme heat or dehydration, or is taking concomitant anticholinergic medication), Method 1 or any of 1.1-1.38.

[0053] 1.41. Method 1.40, wherein the patient was previously treated with another atypical antipsychotic, but the treatment was discontinued due to the development or risk of development of thermoregulation dysregulation.

[0054] 1.42. Method 1, or any of 1.1-1.41, where the patient is switching from treatment with another atypical antipsychotic to treatment with lumateperone (e.g., lumateperone tosylate) and the switch does not involve dose titration.

[0055] 1.43. Any of the above methods wherein the patient has previously been treated with risperidone, aripiprazole, and olanzapine, and / or an atypical antipsychotic such as quetiapine or ziprasidone.

[0056] 1.44. Any of the above methods wherein treatment of the patient with risperidone, aripiprazole, and olanzapine, and / or atypical antipsychotics such as quetiapine or ziprasidone is contraindicated.

[0057] 1.45. Any of the above methods, wherein said method does not cause the patient to develop tardive dyskinesia.

[0058] 1.46. Any of the above methods, wherein the method does not cause the patient to develop hyperglycemia or diabetes mellitus (e.g., as indicated by monitoring fasting plasma glucose, insulin and / or hemoglobin A1c levels).

[0059] 1.47. Any of the above methods, wherein the method does not cause the patient to develop dyslipidemia (e.g., as indicated by monitoring a plasma lipid panel including cholesterol, triglyceride, VLDL, LDL, and HDL levels).

[0060] 1.48. Any of the above methods, wherein the method does not cause the patient to develop weight gain (e.g., compared to the patient's pre-treatment weight and / or relative to the normal body mass index of a person of the patient's height).

[0061] 1.49. Any of the above methods, wherein said method does not cause the patient to experience orthostatic hypertension or syncope.

[0062] 1.50. Any of the above methods, wherein the method further comprises a step of evaluating the patient for signs of cerebrovascular disease, cardiovascular disease, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, and / or orthostatic vital signs prior to initiation of treatment with lumateperone (e.g., lumateperone tosylate).

[0063] 1.51. Any of the above methods, wherein the method further comprises evaluating the patient periodically (e.g., every 1 month, every 2 months, every 3 months, every 4 months, every 6 months, every 9 months, every 12 months, every 18 months, or every 24 months) during treatment with lumateperon tosylate for signs of cerebrovascular disease, cardiovascular disease, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, and / or orthostatic vital signs.

[0064] 1.52. Any of the above methods, wherein the method provides improved sleep (e.g., increased somnolence and / or sedation).

[0065] 1.53. Any of the above methods, wherein the method provides a significant reduction in PANSS total score, e.g., at least a 4-point reduction, or at least a 5-point reduction, or at least a 7-point reduction, or at least a 9-point reduction, or at least a 10-point reduction, or at least a 12-point reduction, or at least a 14-point reduction in PANSS total score, within 28 days of initiating treatment.

[0066] 1.54. Any of the above methods, wherein the method provides a significant reduction in PANSS total score, e.g., at least a 4-point reduction, or at least a 5-point reduction, or at least a 6-point reduction, or at least a 7-point reduction, or at least an 8-point reduction in PANSS total score, within 8 days of initiating treatment.

[0067] 1.55. Any of the above methods, wherein the patient is diagnosed with schizophrenia according to DSM-5 criteria or according to DSM-IV-TR criteria.

[0068] 1.56. Any of the above methods, wherein the patient has a baseline PANSS total score of 60-100 at the start of treatment, e.g., a PANSS total score of 80-90, or 85-95, or 88-90.

[0069] Lumateperone inhibits serotonin 5-HT 2A High binding affinity (K i =0.54 nM and has a moderate binding affinity (K i =32 nM). Lumateperone has a moderate binding affinity (K i =33 nM. Lumateperone also binds to the dopamine D1 receptor (K i =41 nM) and has moderate binding affinity to dopamine D4 receptors, and adrenaline α 1A Receptors and adrenaline alpha 1B Receptor (K iIt has moderate binding affinity to muscarinic and histaminergic receptors (predicted at <100 nM), but low binding affinity to muscarinic and histaminergic receptors (less than 50% inhibition at 100 nM).

[0070] Thus, lumateperone has a very unique receptor binding profile that is not matched by any other existing antipsychotic drug, whether typical or atypical, and yet lumateperone is currently classified as a member of the atypical antipsychotic class.

[0071] The exact mechanism of action of lumateperone in the treatment of schizophrenia is unknown. However, the efficacy of lumateperone may be due to its ability to inhibit central serotonin 5-HT 2A It may be mediated by a combination of antagonist activity at the receptor and postsynaptic antagonist activity at central dopamine D2 receptors.

[0072] Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death. An analysis of 17 placebo-controlled trials (10-week modal duration) found that the risk of death for drug-treated patients was 1.6–1.7 times higher than for placebo-treated patients, primarily in patients receiving atypical antipsychotics. During a typical 10-week controlled trial, the mortality rate for placebo-treated patients was approximately 2.6%, compared with approximately 4.5% for drug-treated patients.

[0073] Causes of death were varied, but in reality most deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia).

[0074] In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke, including fatal stroke, and transient ischemic attack.

[0075] Lumateperone (e.g., lumateperone tosylate) does not appear to pose the same risks as other atypical antipsychotics in elderly patients and patients with dementia-related psychosis. Nevertheless, lumateperone tosylate is not currently approved in the United States for the treatment of patients with dementia-related psychosis.

[0076] Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in association with antipsychotic drug administration. Clinical symptoms of NMS include hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected in a patient, such antipsychotics should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.

[0077] Lumateperone (e.g., lumateperone tosylate) does not appear to pose the same risk of NMS as other atypical antipsychotics.

[0078] Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, can develop in patients treated with antipsychotics. Older people, especially older women, appear to be at greatest risk, but it is not possible to predict which patients will develop the syndrome. It is unclear whether different antipsychotic products differ in their likelihood of causing tardive dyskinesia.

[0079] The risk of tardive dyskinesia and its likelihood of becoming irreversible increase with the duration of treatment and cumulative dose. The syndrome can develop after a relatively short period of treatment, even at low doses. It can also occur after cessation of treatment.

[0080] Tardive dyskinesia may partially or completely remit when antipsychotic treatment is discontinued. However, antipsychotic treatment itself can suppress (or partially suppress) the signs and symptoms of the syndrome, potentially masking the underlying process. The effect of symptom suppression on the long-term course of tardive dyskinesia is unknown.

[0081] Therefore, antipsychotics are generally prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for 1) patients with chronic conditions known to respond to antipsychotics and 2) patients for whom effective, potentially less harmful, alternative treatments are unavailable or inappropriate. In patients requiring chronic treatment, the lowest dose and shortest treatment duration that produces a satisfactory clinical response should be used. The need for continued treatment should be periodically reassessed.

[0082] If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotic medication, discontinuation of the drug should be considered. However, some patients may require treatment with antipsychotic medication despite the presence of the syndrome.

[0083] Antipsychotics have been shown to cause metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all drugs in this class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

[0084] Hyperglycemia, sometimes extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with antipsychotics. Hyperglycemia has been reported in patients treated with lumateperone tosylate. Fasting plasma glucose should be assessed before or shortly after initiating antipsychotic therapy and monitored periodically during long-term treatment.

[0085] Pooled data from short-term (4-6 week) placebo-controlled trials in adult patients with schizophrenia showed that the mean change from baseline and the proportion of patients who shifted from normal to higher fasting glucose levels in patients treated with lumateperone tosylate were similar to those in placebo-treated patients.

[0086] In uncontrolled, open-label studies of lumateperone tosylate in patients with stable schizophrenia for up to 1 year, the proportion of patients with normal-to-high fasting glucose and fasting insulin levels was 8% and 12%, respectively. A total of 4.7% of patients with normal hemoglobin A1c (<6.5%) at baseline experienced elevated levels (≥6.5%) after baseline.

[0087] Antipsychotics cause adverse lipid changes. Patients should have a baseline fasting lipid profile obtained before or shortly after starting antipsychotic medication, and this should be monitored periodically during treatment.

[0088] Pooled data from short-term (4-6 week) placebo-controlled trials in adult patients with schizophrenia showed that mean changes from baseline and proportions of patients with a shift to higher fasting total cholesterol and triglycerides were similar in patients treated with lumateperone tosylate and those treated with placebo.

[0089] In uncontrolled, open-label studies of lumateperone tosylate in patients with stable schizophrenia for up to one year, the proportion of patients who experienced a shift from normal to elevated levels of total cholesterol, triglycerides, and LDL cholesterol was 8%, 5%, and 4%, respectively.

[0090] Weight gain has been observed with antipsychotic use. Patients should monitor their weight at baseline and frequently thereafter. Pooled data from placebo-controlled trials in adult patients with schizophrenia showed that patients treated with lumateperone tosylate and placebo had similar mean changes from baseline and proportions of subjects with a weight gain of ≥7% from baseline to the end of the study.

[0091] In uncontrolled, open-label studies of lumateperone tosylate in patients with stable schizophrenia for up to 1 year, the mean change in body weight was approximately -2 kg (SD 5.6) at day 175 and approximately -3.2 kg (SD 7.4) at day 350.

[0092] Leukopenia and neutropenia have been reported during treatment with antipsychotics, including lumateperon tosylate. Agranulocytosis, including fatal cases, has been reported with other agents in the atypical antipsychotic class.

[0093] Possible risk factors for leukopenia and neutropenia include a preexisting low white blood cell count (WBC) or absolute neutrophil count (ANC) and a history of drug-induced leukopenia or neutropenia. Patients with a preexisting low WBC or ANC or a history of drug-induced leukopenia or neutropenia should have frequent complete blood counts (CBCs) performed during the first few months of treatment. In such patients, discontinuation of treatment should be considered at the first sign of a clinically significant decrease in WBCs in the absence of other causative factors.

[0094] Patients with clinically significant neutropenia should be monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Treatment should be discontinued in patients with absolute neutrophil counts <1000 / mm3, and WBC counts should be followed until recovery.

[0095] Atypical antipsychotics can cause orthostatic hypotension and syncope. Generally, the risk is highest with the initial dose. In clinical trials, the incidence of orthostatic hypotension with lumateperone tosylate and placebo was 0.7% and 0%, respectively. The incidence of syncope with lumateperone tosylate and placebo was 0.2% and 0.2%, respectively.

[0096] Orthostatic vital signs should be monitored in patients prone to hypotension (e.g., elderly, dehydrated, hypovolemic, and concomitantly treated with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Lumateperone tosylate has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from premarketing clinical trials.

[0097] Antipsychotics, including lumateperone (e.g., lumateperone tosylate), can cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures and other injuries. For patients with diseases, conditions, or medications that may exacerbate these effects, complete a fall risk assessment at the initiation of antipsychotic treatment and periodically during long-term treatment.

[0098] Like other antipsychotics, lumateperone (e.g., lumateperone tosylate) has the potential to cause seizures. The risk is highest in patients with a history of seizures or conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more common in elderly patients.

[0099] Lumateperone (e.g., lumateperone tosylate), like other antipsychotics, can cause somnolence, which can impair judgment, thinking, and motor skills. In short-term (i.e., 4-6 weeks) placebo-controlled clinical trials in patients with schizophrenia, somnolence and sedation were reported in 24% of lumateperone tosylate-treated patients compared with 10% of placebo-treated patients.

[0100] Patients taking lumateperone (e.g., lumateperone tosylate) should be warned against operating hazardous machinery, including motor vehicles, until it can be reasonably assured that treatment with lumateperone tosylate will not adversely affect the patient.

[0101] Atypical antipsychotics may disrupt the body's ability to lower core body temperature. Strenuous exercise, exposure to extreme heat and dehydration, and anticholinergic medications may contribute to elevated core body temperature; lumateperone tosylate should be used with caution in patients who may experience these conditions.

[0102] Esophageal motility disorders and aspiration have been associated with the use of antipsychotics. Antipsychotics, including lumateperone (e.g., lumateperone tosylate), should be used with caution in patients at risk for aspiration.

[0103] Concomitant use of lumateperone (e.g., lumateperone tosylate) with moderate or strong CYP3A4 inhibitors may increase lumateperone exposure and increase the risk of adverse reactions. Therefore, such coadministration should be avoided. Moderate CYP3A4 inhibitors include amprenavir, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole, fluvoxamine, and verapamil. Strong CYP3A4 inhibitors include clarithromycin, grapefruit juice, itraconazole, voriconazole, nefazodone, ritonavir, and nelfinavir.

[0104] Concomitant use of lumateperone (e.g., lumateperone tosylate) with CYP3A4 inducers reduces lumateperone exposure; therefore, such use should be avoided. CYP3A4 inducers include carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin, aprepitant, armodafinil, pioglitazone, and prednisone.

[0105] Concomitant use of lumateperone (e.g., lumateperone tosylate) with UGT inhibitors may increase exposure to lumateperone and / or its metabolites. Therefore, such co-administration should be avoided. UGT inhibitors include valproic acid and probenecid.

[0106] Controlled clinical trials of lumateperone tosylate did not include patients aged 65 years or older, making it impossible to determine whether they respond differently from younger patients.

[0107] Antipsychotics increase the risk of death in elderly patients with dementia-related psychosis. Although lumateperon tosylate is not approved for the treatment of dementia-related psychosis, it does not appear to pose the same risk in this regard as other atypical antipsychotics.

[0108] The use of lumateperone (e.g., lumateperone tosylate) is not recommended in patients with moderate hepatic impairment (Child-Pugh class B) to severe hepatic impairment (Child-Pugh class C). Patients with moderate and severe hepatic impairment have increased exposure to lumateperone. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh class A).

[0109] The terms "treatment" and "treating" should be understood accordingly to encompass prevention and treatment or amelioration of symptoms of disease and / or treatment of the cause of disease. In certain embodiments, the terms "treatment" and "treating" refer to prevention or amelioration of symptoms of disease.

[0110] The term "patient" means a human patient.

[0111] The term "adult" means a patient who is at least 18 years of age.

[0112] As used herein without further specification, the term "lumateperone" is understood to encompass lumateperone free base and all pharmaceutically acceptable salts of lumateperone, including, but not limited to, lumateperone tosylate, lumateperone besylate, lumateperone hydrochloride, lumateperone oxalate, lumateperone aminosalicylate, lumateperone cyclamate, lumateperone nosylate, and lumateperone mesylate. In some embodiments, lumateperone in the free base form or a pharmaceutically acceptable salt form is in a crystalline form.

[0113] As used herein, unless otherwise specified, the term "lumateperon tosylate" refers to lumateperon monotosylate, lumateperon bistosylate, or any other acid addition salt form of lumateperon containing toluenesulfonic acid (including salts with a base-to-acid ratio of less than 1:1 and mixed salts containing other acid anions). In some embodiments, references herein to "lumateperon tosylate" may refer to lumateperone monotosylate. Currently, only lumateperone monotosylate has been studied in human clinical trials and has received regulatory approval for administration to humans. Therefore, references herein to "lumateperon tosylate" in relation to clinical trial results and regulatory approvals are understood to refer to lumateperone monotosylate.

[0114] As used herein, a reference to a patient "at risk" of having or developing a side effect or disorder may refer to a patient with a family history of the side effect or disorder, or a patient with symptoms or test results that are consistent with the risk of having or developing the side effect or disorder.Assessing such risk is within the skill of a general practitioner or specialist.For example, a patient at risk of having or developing diabetes can be assessed based on fasting blood glucose level, fasting blood insulin level, glucose tolerance test, serum hemoglobin A1c, family history of diabetes, and other risk factors for diabetes (such as body weight, cardiovascular health, etc.).It is understood that for some of these factors, test results may indicate either the presence of diabetes or an increased risk of developing diabetes. Similarly, patients with or at risk of having dyslipidemia can be evaluated based on fasting blood lipid levels (e.g., cholesterol; HDL, LDL and VLDL lipoproteins; lipoprotein ratio; triglycerides), past medical history of elevated blood lipid levels, and family history of dyslipidemia or heart disease (e.g., ischemic heart disease, coronary artery disease), or genetic mutations associated with lipid disorders.Similarly, patients with or at risk of having liver damage (or the progression of liver damage) can be evaluated based on blood or liver biopsy levels of liver enzymes (e.g., ALT, AST, alkaline phosphatase), or evidence of current or past hepatitis (e.g., circulating antibodies against hepatitis A, B or C antigens), known risk factors for liver damage (e.g., chronic alcoholism), or evidence of early-stage liver disease (e.g., fatty liver disease). Similarly, patients with or at risk of having cognitive or motor dysfunction can be assessed based on the patient's clinical examination (including memory tests and imaging such as CT and MRI, and history of seizures), family history or diagnosis of diseases such as Alzheimer's disease and Parkinson's disease, and history of trauma (such as evidence of acute head trauma or traumatic brain injury).

[0115] References herein to "weight gain" may refer to a change in a patient's weight and / or a comparison of a patient's body mass index (BMI) to a normalized BMI range for the patient's height.

[0116] Methods for synthesizing lumateperone and related compounds are known in the art and include those disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 7,081,455; 8,309,722; U.S. Reissue Patent No. 39680 and U.S. Reissue Patent No. 39679, and U.S. Patent Application Publication No. 2017 / 183350, the contents of each of which are incorporated herein by reference in their entirety. Salts of the compounds of the present invention may also be prepared similarly as described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,648,077; Reissue Patent No. 39680; and Reissue Patent No. 39679, the contents of each of which are incorporated herein by reference in their entirety. [Example]

[0117] Example 1: Clinical trial experience Because clinical trials are conducted under widely different conditions, adverse reaction rates observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

[0118] The safety of lumateperone tosylate (specifically lumateperone monotosylate) has been evaluated in 1,724 adult patients with schizophrenia who were exposed to one or more doses. Of these patients, 811 participated in short-term (4-6 week) placebo-controlled trials at doses ranging from 14 to 84 mg / day. A total of 329 lumateperone tosylate-exposed patients were exposed to lumateperone tosylate 60 mg for at least 6 months, and 108 were exposed for at least 1 year.

[0119] No adverse reactions leading to discontinuation occurred in >2% of patients treated with lumateperone tosylate.

[0120] The most common adverse reactions (incidence of at least 5% of subjects exposed to lumateperon tosylate and greater than twice that of placebo) were somnolence / sedation and dry mouth.

[0121] Adverse reactions associated with lumateperon tosylate (incidence of at least 2% of patients exposed to lumateperon tosylate and greater than placebo) are shown in the table below. The following findings are based on pooled, short-term (4-6 week), placebo-controlled studies (N=406) in adult patients with schizophrenia receiving lumateperon tosylate at a daily dose of 42 mg. [Table 1]

[0122] Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, can occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include neck muscle spasms, sometimes progressing to a tight throat, difficulty swallowing, difficulty breathing, and / or tongue protrusion. While these symptoms can occur at low doses, they occur more frequently and with greater severity with the increased potency and dose of first-generation antipsychotics. An increased risk of acute dystonia has been observed in men and younger individuals.

[0123] Extrapyramidal Symptoms: In 4- to 6-week placebo-controlled trials, the reported frequency of events related to extrapyramidal symptoms (EPS), including akathisia, extrapyramidal disturbances, muscle cramps, restlessness, musculoskeletal stiffness, dyskinesia, dystonia, muscle spasms, tardive dyskinesia, tremor, salivation, and involuntary muscle contractions, was 6.7% for lumateperone tosylate and 6.3% for placebo.

[0124] During the 4- to 6-week study, data were collected using the Simpson-Angus Scale (SAS) for EPS (total score ranges from 0 to 40), the Barnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to 14), and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia (total score ranges from 0 to 28). The mean changes from baseline for lumateperone tosylate- and placebo-treated patients were 0.1 and 0 for SAS, -0.1 and 0 for BARS, and 0.1 and 0 for AIMS, respectively.

[0125] QTcF interval was assessed in 33 patients with schizophrenia in a placebo- and active (moxifloxacin 400 mg)-controlled, randomized, four-arm crossover study utilizing concentration-QTc effect modeling. Placebo-corrected changes in QTcF interval from baseline were 4.9 (8.9) and 15.8 (19.8) ms (90% two-sided upper confidence interval) for lumateperon tosylate 42 mg and a supratherapeutic dose of 126 mg (three times the recommended daily dose) administered orally once daily for 5 days.

[0126] Specifically, lumateperone tosylate was evaluated for the treatment of schizophrenia in two placebo-controlled trials.

[0127] Study 1 (NCT01499563) was a 4-week, randomized, double-blind, placebo-controlled, multicenter trial in adult patients diagnosed with schizophrenia according to DSM-IV-TR criteria. The primary efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale used to measure symptoms of schizophrenia. Each item is rated by a clinician on a 7-point scale. A score of 1 indicates no symptoms, and a score of 7 indicates very severe symptoms. PANSS total scores can range from 30 to 210, with higher scores reflecting greater overall symptom severity.

[0128] A total of 335 patients were randomized to receive lumateperon tosylate 42 mg, lumateperon tosylate 84 mg (twice the recommended daily dose), an active comparator, or placebo. The study was not designed to compare the efficacy of lumateperon tosylate with that of the active comparator. Demographic and baseline disease characteristics for the lumateperon tosylate, active comparator, and placebo groups were similar. The median age was 42 years (range, 20-55 years). 17% were women, 19% were Caucasian, and 78% were African American.

[0129] Patients randomized to lumateperon tosylate 42 mg demonstrated a statistically significant reduction in PANSS total score compared with the placebo group from baseline to Day 28. The treatment effect (vs. placebo) in the lumateperon tosylate 84 mg group was not statistically significant.

[0130] Study 2 (NCT02282761) was a 4-week, randomized, double-blind, placebo-controlled, multicenter trial in adult patients diagnosed with schizophrenia according to DSM-5 criteria. The primary efficacy outcome was the PANSS total score.

[0131] A total of 450 patients were randomized to receive lumateperon tosylate 28 mg (two-thirds the recommended daily dose), lumateperon tosylate 42 mg, or placebo. Demographic and baseline disease characteristics for the lumateperon tosylate and placebo groups were similar. The median age was 44 years (range 19-60 years), 23% were female, 26% were white, and 66% were African American.

[0132] Patients randomized to lumateperon tosylate 42 mg demonstrated a statistically significant reduction in PANSS total score compared with the placebo group from baseline to Day 28. The treatment effect (vs. placebo) in the lumateperon tosylate 28 mg group was not statistically significant.

[0133] The results of Test 1 and Test 2 are shown in the table below: [Table 2]

[0134] PANSS total scores can range from 30 to 210; higher scores reflect greater symptom severity. SD: standard deviation; SE: standard error; LSmean: least squares mean; CI: unadjusted confidence interval. a LS mean change difference from baseline (drug minus placebo) unadjusted for increased sample size after open-label interim analysis. * Statistically significantly superior to placebo.

[0135] Trials 1 and 2 did not include patients over the age of 65. Examination of racial and gender subgroups did not suggest differences in response in either trial.

[0136] Figure 3 shows the change over time from baseline in the PANSS total score of schizophrenia patients in Study 2.

[0137] Example 2: Pharmacokinetic study Following once-daily oral administration of lumateperone tosylate, steady-state lumateperone exposure is achieved in approximately 5 days. Increases in steady-state exposure are approximately dose-proportional over the 21 mg to 56 mg range. Significant intersubject variability in lumateperone PK parameters was observed, with C max The coefficients of variation for (peak plasma concentrations) and AUC (area under the concentration versus time curve) ranged from 68% to 97% at steady state.

[0138] Absorption: The absolute bioavailability of lumateperone capsules is approximately 4.4%. max is reached approximately 1 to 2 hours after administration of lumateperon tosylate.

[0139] Food effect: When a high-fat meal is ingested with lumateperone tosylate, the lumateperone mean C max The mean AUC decreased by 33% and increased by 9%. max The median time was delayed by approximately 1 hour (from 1 hour in the fasted state to 2 hours in the presence of food).

[0140] Distribution: Lumateperone protein binding is 97.4% at 5 μM in human plasma (approximately 70-fold higher than the therapeutic concentration). The volume of distribution of lumateperone after intravenous administration is approximately 4.1 L / kg.

[0141] Elimination: Lumateperone has a clearance of approximately 27.9 L / hour and a terminal half-life of approximately 18 hours after intravenous administration.

[0142] Metabolism: Lumateperone is extensively metabolized, with over 20 metabolites identified in vivo. 14After oral administration of C-labeled lumateperone, lumateperone and glucuronidated metabolites account for approximately 2.8% and 51% of total plasma radioactivity, respectively. In vitro studies have shown that multiple enzymes are involved in the metabolism of lumateperone, including, but not limited to, uridine 5'-diphospho-glucuronosyltransferases (UDP-glucuronosyltransferases, UGTs) 1A1, 1A4, and 2B15, aldo-ketoreductases (AKRs) 1C1, 1B10, and 1C4, and cytochrome P450 (CYPs) 3A4, 2C8, and 1A2.

[0143] Excretion: In a human mass balance study, 58% and 29% of the radioactive dose was recovered in the urine and feces, respectively. Less than 1% of the administered dose was excreted in the urine as unchanged lumateperone.

[0144] Specific Populations: The effect of hepatic or renal impairment on lumateperone exposure is shown in Figure 1. No clinically significant differences in lumateperone pharmacokinetics were observed by age, sex, or race.

[0145] Drug Interaction Studies: The effects of other drugs on lumateperone exposure are shown in Figure 2. CYP3A4 Substrates: No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A4 substrate) or its metabolite, 1-hydroxymidazolam, were observed when coadministered with single or multiple doses of lumateperone in patients with schizophrenia.

[0146] In vitro studies: Lumateperone showed little inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 / 5. It also showed no induction of CYP1A2, CYP2B6, or CYP3A4. Lumateperone does not appear to be a P-gp or BCRP substrate. It showed little inhibition of OCT2, OAT1, OAT3, OATP1B3, or OATP1B1.

Claims

1. A pharmaceutical product for use in a method of treating schizophrenia in adult patients, comprising lumateperone or lumateperone tosylate, wherein the method of treatment comprises administering an oral daily dose of 42 mg of lumateperone or 60 mg of lumateperone tosylate in capsule form to a patient requiring such treatment, and the method does not involve dose titration.

2. The pharmaceutical product according to claim 1, wherein a patient is being switched from treatment with another atypical antipsychotic to treatment with lumateperone tosylate, and the switch does not involve dose titration.

3. The pharmacopoeia according to claim 2, wherein the previous atypical antipsychotic was risperidone, aripiprazole, olanzapine, quetiapine, or ziprasidone.

4. The pharmacopoeia according to claim 2, wherein the use of atypical antipsychotics was discontinued due to the development or risk of developing moderate or severe hepatic impairment.

5. The pharmacopoeia according to claim 2, wherein the previous use of an atypical antipsychotic was discontinued due to the need for concomitant treatment with a CYP3A4 inducer, a moderate or potent CYP3A4 inhibitor and / or a UGT inhibitor, or due to side effects resulting from concomitant treatment with a CYP3A4 inducer, a moderate or potent CYP3A4 inhibitor and / or a UGT inhibitor.

6. The pharmacopoeia according to claim 2, wherein the use of atypical antipsychotics was discontinued due to the development or risk of developing hyperglycemia or diabetes mellitus.

7. The pharmacopoeia according to claim 2, wherein the use of atypical antipsychotics was discontinued due to the onset or risk of weight gain.

8. The pharmacopoeia according to claim 2, wherein the use of atypical antipsychotics was discontinued due to the development or risk of developing leukopenia, neutropenia, and / or agranulocytosis.

9. A pharmaceutical product according to any one of claims 1 to 8, which is taken orally in a daily dose with food.

10. A pharmaceutical product according to any one of claims 1 to 9, wherein the daily oral dose of lumateperone 42 mg (lumateperone tosylate 60 mg) is provided as one capsule, and the capsule may further contain croscarmellose sodium, gelatin, magnesium stearate, mannitol, talc, and a coloring agent.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the patient has not received concomitant treatment with a CYP3A4 inducer, a moderate or potent CYP3A4 inhibitor, and / or a UGT inhibitor.

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the patient does not have moderate or severe hepatic impairment, or the patient has mild hepatic impairment.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the patient has hyperglycemia or diabetes mellitus or is at risk of developing such conditions, or the patient has a history of hyperglycemia or diabetes mellitus.

14. The pharmaceutical product according to any one of claims 1 to 13, wherein the patient is overweight or at risk of developing weight gain, or the patient has a history of difficulty in managing weight.

15. The pharmaceutical product according to any one of claims 1 to 14, wherein the method does not cause weight gain in the patient.

16. The pharmacopoeia according to any one of claims 1 to 15, wherein the method provides a reduction of at least 4 points in the total PANSS score within 28 days from the start of treatment.

17. The pharmacopoeia according to any one of claims 1 to 16, wherein the method provides a reduction of at least 4 points in the total PANSS score within 8 days of the start of treatment.

18. A pharmaceutical product according to any one of claims 1 to 17, wherein the patient has a baseline PANSS total score of 60 to 100 at the start of treatment.

19. A pharmaceutical product according to any one of claims 1 to 18, wherein the patient is diagnosed with schizophrenia according to the DSM-5 criteria or the DSM-IV-TR criteria.

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