Method of treatment with milsaperidone

Abstract

Described herein is an improved method of treatment of major depressive disorder with an antidepressant, comprising administration of an effective dose of milsaperidone as an adjunctive therapy.

Description

METHOD OF TREATMENT WITH MILSAPERIDONECROSS REFERENCE TO RELATED APPLICATION

[0001] The present international patent application claims priority to US provisional patent application no. 63 / 746,910, filed January 17, 2025.FIELD OF DISCLOSURE

[0002] The disclosure relates generally to the treatment of major depressive disorder (MDD). More particularly, the disclosure relates to the use of milsaperidone as an adjunctive treatment to improve treatment effect of antidepressant therapy for MDD.BACKGROUND

[0003] Major depressive disorder (MDD) is a complex and serious mental health condition defined by persistently low or depressed mood, loss of interest in activities that once brought joy, physical and cognitive symptoms, and recurrent thoughts of death. Persons suffering from MDD have reduced quality of life, high rates of medical comorbidities, and poor outcomes due to social effects and functional impairment. According to a 2018 WHO World Mental Health Survey, MDD has a -10% global lifetime prevalence, although this is likely an underestimate of the true worldwide incidence, with prospective studies pointing to >30% lifetime prevalence, and a 4-5% estimated 12-month prevalence from shorter time frame studies. Risk of suicide has been estimated to be 20 times higher than in those without the condition, and MDD is the highest contributing factor in terms of years of life lost to suicide.

[0004] The underlying causes of MDD are not fully understood, but dysregulation of neurotransmitter systems of central serotonin (5HT), norepinephrine (NE), and dopamine (DA) receptors are believed to play a major role. These represent the major targets of first line pharmacological antidepressants including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) and in treatment resistant cases, adjunctive therapies such as antipsychotics. Despite established efficacy of antidepressants, the majority of patients (68%) fail to achieve remission following treatment with a first line antidepressant, while up to 30% of patients fail to respond adequately to treatment following treatment with two antidepressant regimens.

[0005] Milsaperidone (l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanol), or 4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]propoxy]-3-methoxy-a-methylbenzenem ethanol), also known as VHX-896, P88, (S)-P-88-8891, or S-P88, is one of two major circulating metabolites of iloperidone, an atypical antipsychotic. FANAPT® iloperidone is approved for the treatment of acute schizophrenia in adults (May 2009), maintenance treatment of schizophrenia in adults (May 2016), and most recently treatment of acute manic or mixed episodes associated with bipolar I disorder in adults (April 2024). (FANAPT® is a registered trademark of Vanda Pharmaceuticals Inc., Washington, DC, USA.) Milsaperidone has a similar receptor binding profile to iloperidone, including centrally acting 5HT2A, D2, and NEal receptor antagonism. Milsaperidone is known to interconvert with iloperidone in vivo.

[0006] Milsaperidone is disclosed in US Patent Nos. 8,314,129 and 7,977,356. In humans, P88 is only found in the S-enantiomeric form (milsaperidone), which has the following structure:However, P88 can also be synthesized in its R enantiomeric form, which has the structure:P88, and the S and R forms thereof, are described in US Patent Nos. 7,977,356; 8,314,129; and 10,874,659.

[0007] Previous studies have investigated associations between iloperidone efficacy and polymorphisms in genes and gene regions including CFTR, NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1. These associations are described in, e.g., US Patent Nos.9,328,387; 9,458,507; and 9,080,214. Additionally, associations between CYP2D6 andKCNQ1 genotypes and changes in QT interval following the administration of iloperidone are described in US Patent Nos. 8,586,610; 9,138,432; 8,999,638; 9,157,121; and 10,563,259. Further associations between genetic variations in SLCO3A1, BAB, CERKL, FAM13A1, and ABCC2 genes and changes in QT interval following the administration of iloperidone are described in US Patent Nos. 8,652,776; 9,072,742; 9,074,254; 9,074,255; and 9,074,256. Exemplary findings such as these, relating to the safety and efficacy of iloperidone and milsaperidone, aid in selection of the most optimal drug and dosage regimen for a particular patient. This in turn aids in safe and effective treatment of symptoms, diseases, and disorders, with less trial and error, and a reduction in deleterious side effects.BRIEF DESCRIPTION

[0008] Various aspects disclosed herein relate to improved methods for the treatment of major depressive disorder (MDD) in a patient in need thereof. In particular, aspects of the disclosure provide an improvement in methods of treatment of MDD with antidepressants, comprising the addition of adjunctive treatment with milsaperidone. Adjunctive treatment with milsaperidone may improve treatment effect and symptom control beyond what is attainable with antidepressant monotherapy.

[0009] In a first aspect, an improvement is provided for use in a method consisting essentially of treating major depressive disorder (MDD) in a patient in need thereof with an antidepressant. The improvement comprises administering to the patient an adjunctive treatment comprising an effective dose of milsaperidone. This improvement may result in an improved therapeutic response relative to a therapeutic response achieved or achievable with the method of treating MDD with the antidepressant as a monotherapy.

[0010] A second aspect provides a method of treating major depressive disorder (MDD) in a patient in need thereof, comprising administering to the patient an effective dose of an antidepressant; and administering to the patient an effective dose of milsaperidone as an adjunctive therapy.

[0011] In certain embodiments, the antidepressant is selected from the group consisting of bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, and vortioxetine. Treatment with the antidepressant continues during administration of milsaperidone.

[0012] In certain embodiments, the effective dose of milsaperidone may be 12 mg / day, e.g., 12 mg qd if and because the patient has a CYP2D6 non-poor metabolizer genotype, or 6 mg bid if and because the patient has a CYP2D6 poor metabolizer genotype or an unknown CYP2D6 metabolizer genotype. The effective dose of 12 mg / day may further be given as 6 mg bid if and because the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3 A4 inhibitor. Exemplary CYP2D6 inhibitors include, e.g., thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine. Exemplary CYP3A4 inhibitors include, e.g., Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafarnib, Amprenavir, Amiodarone, and Levoketoconazole.

[0013] A third aspect provides a method of initiating adjunctive treatment of major depressive disorder (MDD) with milsaperidone in a patient in need thereof, comprising administering milsaperidone at a dose of 2 mg / day on day 1; administering milsaperidone at a dose of 4 mg / day on day 2; administering milsaperidone at a dose of 8 mg / day on day 3; and administering milsaperidone at a dose of 12 mg / day on each of days 4-7. In certain embodiments, the patient is stabilized on treatment with an antidepressant prior to initiating the adjunctive treatment.

[0014] In certain embodiments, the dose of 2 mg / day milsaperidone on day 1 is given as 1 mg bid; the dose of 4 mg / day on day 2 is given as 2 mg bid; the dose of 8 mg / day on day 3 is given as 4 mg bid; and the dose of 12 mg / day on each of days 4-7 is given as 6 mg bid.

[0015] In certain embodiments, the method further comprises administering milsaperidone at a dose of 12 mg / day on day 8 and onward.

[0016] In certain embodiments, the method further comprises determining whether the patient is a CYP2D6 poor metabolizer by obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype. Ifthe patient has a CYP2D6 non-poor metabolizer genotype, the dose of 12 mg / day on each of days 8 onward may be 12 mg qd. If the patient has a CYP2D6 poor metabolizer genotype, the dose of 12 mg / day on each of days 8 onward may be 6 mg bid. If the patient is concurrently being administered a CYP2D6 inhibitor, the dose of 12 mg / day on each of days 8 onward may be 6 mg bid.

[0017] A fourth aspect provides milsaperidone for use in the treatment of major depressive disorder (MDD) in a patient in need thereof, the treatment comprising administration to the patient of an effective dose of milsaperidone, wherein the milsaperidone is as an adjunctive therapy to treatment with an effective dose of an antidepressant.

[0018] A fifth aspect provides for use of milsaperidone for the manufacture of a medicament for use in the treatment of major depressive disorder (MDD) in a patient in need thereof, the treatment comprising administration to the patient of an effective dose of milsaperidone, wherein the milsaperidone is as an adjunctive therapy to treatment with an effective dose of an antidepressant.

[0019] In certain embodiments, initiating the adjunctive treatment results in an improved therapeutic response relative to a therapeutic response achieved or achievable with treatment of the MDD with the antidepressant as a monotherapy.

[0020] These and other aspects, advantages and salient features of the disclosure will become apparent from the following detailed description, which, when taken in conjunction with the annexed drawings, where like parts are designated by like reference characters throughout the drawings, disclose embodiments of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 provides a schematic depiction of the design of the study in Example 1.

[0022] FIG. 2 provides a flow chart for treatment assignment in the study of Example 1, based on CYP2D6 metabolizer status and concomitant antidepressant use.

[0023] The drawings are intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure.DETAILED DESCRIPTION

[0024] In various embodiments of the disclosure, improved methods are described herein for treatment of major depressive disorder (MDD) with antidepressants, in which milsaperidone is administered as an adjunct therapy. Such methods result in improved treatment response relative to treatment of MDD with antidepressants as a monotherapy.

[0025] As used herein, the terms “patient,” “subject,” and “individual” refer to a mammal that is afflicted with one or more disorders ameliorated by administration of milsaperidone or iloperidone such as, e.g., major depressive disorder (MDD), particularly MDD for which antidepressant monotherapy has not provided an adequate treatment response. Other disorders ameliorated by administration of milsaperidone or iloperidone include schizophrenia, a schizophreniform disorder, bipolar I disorder, acute manic and mixed episodes associated with bipolar I disorder, agitation associated with Alzheimer’s Disease, agitation associated with dementia, agitation associated with autism, Parkinson’s Disease Psychosis, or another psychotic disease or disorder. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of mammals within the scope of the meaning of the term. It will be understood that the most preferred patient is a human. A “patient in need of treatment with” iloperidone or milsaperidone refers to a patient suffering from, or diagnosed with a condition that is understood by a person of skill in the art, to be treated or treatable with iloperidone, milsaperidone, or a pharmaceutically acceptable salt of iloperidone or milsaperidone, such as (but not limited to) those conditions listed above.

[0026] It is also recognized that one skilled in the art may affect the disorders discussed herein by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of iloperidone, milsaperidone, or a pharmaceutically acceptable salt of iloperidone or milsaperidone. Thus, the terms “treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the diseases or disorders described herein, or a reduction in the frequency of episodes thereof, and is intended to include prophylactic treatment of such disorders. “Treatment” does not necessarily indicate a total elimination of all disorder symptoms, and may include improvement therein.

[0027] As used herein, the term “effective amount” as it relates to iloperidone,milsaperidone, or a pharmaceutically acceptable salt of iloperidone or milsaperidone, refers to an amount of the compound that is effective in treating the disorders described herein. Exemplary effective amounts or effective doses of milsaperidone may be, e.g., about 1 mg / day to about 500 mg / day, or about 1 mg / day to about 300 mg / day, which may be administered, for example, in divided doses up to four times a day or in sustained release form. In particular, exemplary effective amounts, or effective doses of milsaperidone may be, e.g., 12 mg / day to 24 mg / day, which may be given in twice daily divided doses, e.g., 6 mg twice daily (bid) to 12 mg bid, and may particularly be, e.g., 12 mg / day, 14 mg / day, 16 mg / day, 18 mg / day, 20 mg / day, 22 mg / day, or 24 mg / day, which may be given in twice daily divided doses as 6 mg bid, 7 mg bid, 8 mg bid, 9 mg bid, 10 mg bid, 11 mg bid, or 12 mg bid, following titration. Non-limiting exemplary effective amounts, or effective doses of iloperidone are disclosed in, e.g., US Pat. No. 8,586,610; 9,138,432; 10,272,076; 10,441,580; and 10,987,346. Exemplary effective amounts or effective doses of iloperidone may be, e.g., 12 mg / day to 24 mg / day, which may be given in twice daily divided doses, e.g., 6 mg twice daily (bid) to 12 mg bid, and may particularly be, e.g., 12 mg / day, 14 mg / day, 16 mg / day, 18 mg / day, 20 mg / day, 22 mg / day, or 24 mg / day, which may be given as 6 mg bid, 7 mg bid, 8 mg bid, 9 mg bid, 10 mg bid, 11 mg bid, or 12 mg bid, following titration.

[0028] With regard to dosing, qd (quaque die) refers to dosing once per day; and bid (bis in die) dosing typically means dosing once in the morning and once in the evening, generally no less than about 8 hours or more than about 16 hours apart, e.g., 10 to 14 hours apart, or 12 hours apart (Q12H).

[0029] As used herein, the terms “first,” “second,” and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another, and the terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). The suffix “(s)” as used herein is intended to include both the singular and the plural of the term that it modifies, thereby including one or more of that term (e.g., the milestone(s) includes one or more milestones). Ranges disclosed herein are inclusive and independently combinable (e.g., ranges of “up to about 25 mg, or, more specifically, about 5 mg to about 20 mg,” is inclusive of the endpoints and all intermediate values of the ranges of “about 5 mg toabout 25 mg,” etc.).

[0030] According to embodiments of the disclosure, an improved method is described herein for treating major depressive disorder (MDD) with an antidepressant in a patient in need thereof. The patient may be in need of such treatment, e.g., following a determination that the patient is experiencing an inadequate treatment response to the antidepressant therapy. For example, the patient may have experienced less than 50% improvement in MDD symptoms as assessed on an Antidepressant Treatment Response Questionnaire (ATRQ), after taking at least the minimum effective dose for the antidepressant, for a period of, e.g., six (6) weeks. The antidepressant may be, e.g., bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, and vortioxetine.

[0031] The improved method provided herein includes administering to the patient an adjunctive treatment comprising an effective dose of milsaperidone. According to the improved method, the antidepressant therapy is maintained concurrently with the milsaperidone treatment. The effective dose of milsaperidone may be, e.g., 12 mg / day, which may be reached following a titration period.

[0032] Following identification of an individual in need of treatment with milsaperidone, the method includes determining the CYP2D6 genotype of the individual. The determining step may particularly be performed prior to administering the milsaperidone, or during the titration period. In certain embodiments, such a determination may be made by obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the individual has a CYP2D6 variant genotype. In this context, “obtaining” may refer to collecting or acquiring a biological sample from the patient, while “having obtained” may refer to referring, instructing, or otherwise causing another individual, e.g., a medical or healthcare professional, to perform the obtaining. “Having obtained” may also refer to having previously caused the obtaining to have been performed. For example, an assay that identifies the individual’s CYP2D6 genotype may have been performed in the past, and the result may be reviewed in the individual’s medical records. Similarly, in this context, “performing the genotyping assay” may refer to physically performing the steps to examine the individual’s DNA using a genotyping assay, while “having performed” may refer to referring, instructing, or otherwise causing another individual, e.g., a medical or healthcareprofessional, to carry out the performing. The expression, “having performed” may also refer to having previously caused the performance of the assay. Performing (or having performed) the assay may include the steps of extracting or having extracted genomic DNA or mRNA from the biological sample, and sequencing or having sequenced CYP2D6 DNA derived from the extracted genomic DNA or from the extracted mRNA. The sequencing (or having sequenced) step may further comprise amplifying or having amplified a CYP2D6 region in the extracted genomic DNA or mRNA to prepare a DNA sample enriched in DNA from the CYP2D6 gene region; and sequencing (or having sequenced) the DNA sample by hybridizing the DNA sample to nucleic acid probes to determine if the patient has a CYP2D6 variant genotype. In certain embodiments, the CYP2D6 variant genotype detected in a selected individual may include one or more copies of an allele(s) selected from *3, *4, *5, *6, *7, *8, *9, *10, *17, or *41, as shown in Table 1. Other variants may also be known and understood by one of skill in the art, as discussed above.> > >> > > >> > > > > >> >> >>

[0033] The improved method may further include administering milsaperidone to the individual at an effective a dose that is determined based upon the individual’s CYP2D6 genotype. In certain embodiments, the effective dose of milsaperidone may be 12 mg / day. In a case in which the individual has a CYP2D6 genotype associated with normal metabolism of milsaperidone, i.e., a non-poor metabolizer (non-PM) genotype, the effective dose may be 12 mg / day given as 12 mg qd. Such a dose may be administered to an individual having, e.g., a CYP2D6*1 / *1 genotype, a CYP2D6*l / *2 genotype, or a CYP2D6*2 / *2 genotype.

[0034] In a case in which the individual has a CYP2D6 genotype that is associated with decreased metabolism of milsaperidone relative to wildtype, e.g., a CYP2D6 poor metabolizer (PM) genotype, then the effective dose may be 12 mg / day given as 6 mg bid. Examples of CYP2D6 genotypes that are associated with decreased metabolism of milsaperidone relative to wildtype include CYP2D6 genotypes that include one allele selected from *3, *4, *5, *6, *7, *8, *9, *10, *17, and *41, or two alleles independently selected from *3, *4, *5, *6, *7, *8, *9, *10, *17, and *41.

[0035] The improved method may further include determining whether the patient is being administered one or more medications that are a CYP2D6 inhibitor or a CYP3 A4 inhibitor. Such a determination may be made, e.g., by asking the patient or a guardian of the patient for a list of current medications and reviewing the same, or reviewing the patient’s medical history and records. Examples of CYP2D6 inhibitors include, e.g., thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine. Examples of CYP3A4 inhibitors include, e.g., Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafarnib, Amprenavir, Amiodarone, and Levoketoconazole. In certain embodiments, the effective dose of milsaperidone for the patient is 12 mg / day given as 6 mg bid where the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3 A4 inhibitor. If no CYP2D6 or CYP3 A4 inhibitors are being administered, and the patient is not a CYP2D6 poor metabolizer, the effective dose may be 12 mg / day given as 12 mg qd.

[0036] The administration of milsaperidone as an adjunct to antidepressant therapyfor the treatment of MDD as described herein may result in an improved therapeutic response relative to the therapeutic response achieved or achievable with treatment of MDD with antidepressant monotherapy. This may include more complete control of symptoms of MDD, and greater attainment of MDD treatment goals.

[0037] A further embodiment of the disclosure provides a method of treating major depressive disorder (MDD) in a patient in need thereof. The method comprises administering to the patient an effective dose of an antidepressant such as, e.g., e.g., bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, and vortioxetine. The antidepressant treatment may be administered for a duration of about 4-8 weeks, e.g., about 6 weeks, and may be administered according to the prescribing instructions for the particular antidepressant.Nevertheless, the antidepressant therapy of MDD may result in incomplete or inadequate treatment of MDD symptoms in a significant number of patient cases. Accordingly, the present method further includes administering to the patient an effective dose of milsaperidone as an adjunctive therapy to the antidepressant therapy.

[0038] The present method may include determining the patient’s CYP2D6 genotype as described herein, as well as determining whether the patient is being administered any medications which are CYP2D6 inhibitors or CYP3 A4 inhibitors. The dosing regimen of milsaperidone may be selected based on these determinations. For example, the effective dose of milsaperidone may be, e.g., 12 mg / day, which may be given as 12 mg qd if and because the patient has a CYP2D6 non-poor metabolizer genotype. The effective dose of 12 mg / day may be given as 6 mg bid if and because the patient has a CYP2D6 poor metabolizer genotype or an unknown CYP2D6 metabolizer genotype, e.g., if the patient’s CYP2D6 genotype determination has not been made or has not been completed. Examples of CYP2D6 poor metabolizer genotypes include those having one allele selected from *3, *4, *5, *6, *7, *8, *9, *10, *17, and *41, or two alleles independently selected from *3, *4, *5, *6, *7, *8, *9, *10, *17, and *41. Examples of CYP2D6 non-poor metabolizer genotypes include those having two alleles independently selected from *1 or *2, i.e., a CYP2D6 genotype of CYP2D6*1 / *1, CYP2D6*l / *2, CYP2D6*2 / *1, or CYP2D6 *21*2. Further, the effective dose of 12 mg / day of milsaperidone may be given as 6 mg bid if and because the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3 A4 inhibitor. Examples of CYP2D6 inhibitors include, e.g., thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine. Examples of CYP3 A4 inhibitorsinclude, e.g., Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafamib, Amprenavir, Amiodarone, and Levoketoconazol e .

[0039] Further embodiments of the disclosure include methods for initiating adjunctive treatment of major depressive disorder (MDD) with milsaperidone in a patient in need thereof, as described herein. Such a patient in need of treatment with milsaperidone may be undergoing treatment for MDD with an antidepressant such as, e.g., one of bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine, and may have been treated with such antidepressant for a period of 4-8 weeks, e.g. about 6 weeks. In such time, the patient may have experienced inadequate treatment or control of symptoms of MDD, e.g., 50% or less reduction in symptoms since commencement of treatment with the antidepressant. The patient may further be deemed to be stabilized on treatment with the antidepressant at that level of symptom control.

[0040] Provided herein are methods for safely and effectively initiating adjunctive treatment of such individual’s MDD with milsaperidone. The milsaperidone may be administered at a dose that increases daily up to an eventual daily dose of 12 mg / day via a fixed titration regimen. For example, the patient may be administered milsaperidone at a dose of 2 mg / day on day 1; 4 mg / day on day 2; 8 mg / day on day 3; and 12 mg / day on each of days 4-7. This titration regimen may be administered as, e.g., 1 mg bid; 2 mg bid; 4 mg bid; and 6 mg bid on days 1, 2, 3, and 4-7, respectively.

[0041] The method for initiating adjunctive treatment may further include determining the patient’s CYP2D6 metabolizer status, e.g., whether the patient is a CYP2D6 poor metabolizer. This may include obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype, as described herein above. The determining may further include determining whether the patient is being administered a drug that is a CYP2D6 inhibitor or a CYP3A4 inhibitor, as further described herein above.

[0042] The fixed titration regimen on days 1-7, described above, may be administeredwithout regard for CYP2D6 metabolizer status, and further without regard for CYP2D6 or CYP3 A4 inhibitor co-administration. Beginning on day 8, patients may be administered milsaperidone at a dose of 12 mg / day. However, the dosing frequency may vary with CYP2D6 metabolizer status. For example, for patients having a CYP2D6 non-poor metabolizer (non-PM) genotype, the dose of 12 mg / day may be given as 12 mg qd. For patients having a CYP2D6 poor metabolizer (PM) genotype, the dose of 12 mg / day may be given as 6 mg bid. The latter dose of 6 mg bid may also be administered on days 8 and onward to patients who are concurrently being administered a CYP2D6 inhibitor or a CYP3A4 inhibitor. Exemplary CYP2D6 inhibitors include, e.g., thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine. Exemplary CYP3A4 inhibitors include Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafamib, Amprenavir, Amiodarone, and Levoketoconazol e .

[0043] The use of a fixed titration regimen as described herein allows for the safe initiation of treatment with milsaperidone, by limiting certain side effects that may otherwise result from initiating treatment at a full effective dose. Such side effects may include, e.g., orthostatic hypotension, dizziness, dry mouth, sedation, and extension or elongation of QT interval. The titration regimen further provides a safe path to reaching an effective dose of milsaperidone in about one week, allowing patients to take advantage of the benefits of milsaperidone adjunctive therapy for MDD as compared to treatment of MDD with an antidepressant as a monotherapy.

[0044] The skilled artisan will appreciate that additional preferred embodiments may be selected by combining the preferred embodiments above, or by reference to the examples given herein.EXAMPLESExample 1: Milsaperidone as Adjunctive Therapy in Patients with MDD

[0045] A multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluates the efficacy and safety of milsaperidone for 6 weeks as an adjunctivetreatment to antidepressant therapy (ADT) for patients with Major Depressive Disorder (MDD) that have had an inadequate response to previous ADT.

[0046] With reference to the trial schema depicted in FIG. 1, the study consists of three phases: the Pre-Randomization Phase, the Short-Term Study Treatment Phase, and an optional Open-Label Extension (OLE) Phase. The Pre-Randomization Phase includes the Screening Visit and the Baseline visit. The Short-Term Study Treatment Phase includes a Double-Blind (DB) Titration Period and a Double-Blind Study Treatment Period. The optional OLE Phase also includes two periods: (1) the OLE Titration Period and (2) the OLE Maintenance Period. Approximately 500 patients satisfying the inclusion / exclusion criteria are enrolled into the study, with representative demographics of the Major Depressive Disorder population.

[0047] The Pre-Randomization Phase lasts up to two weeks and begins at the screening visit (Day -14 to -1). During this phase, informed consent is obtained from potential patients and initial eligibility to enter the study is assessed. Evaluations are performed, including collecting blood samples for CYP2D6 genotyping. Patients meeting eligibility criteria continue to the baseline visit. Non-exhaustive diagnostic and clinical criteria for inclusion in the study include: meeting the DSM-5-TR criteria for MDD; the start of the current major depressive episode (MDE) being at least 8 weeks but no more than 24 months prior to screening; rater-administered Montgomery-Asberg Depression Rating Scale (MADRS) total score > 24 at Screening and at Baseline; CGI-S - Severity of Illness score of > 4 at Screening and Baseline; Quick Inventory of Depressive Symptomatology-Self Report- 16 item (QIDS-SR-16) score > 14 at Screening and at Baseline; and current inadequate response to antidepressant therapy (less than 50% improvement) as confirmed by the Investigator using the Antidepressant Treatment Response Questionnaire (ATRQ) and taking at least the minimum effective dose (per package insert) of one of the following antidepressants as monotherapy treatment for at least 6 weeks duration prior to the Screening visit: bupropion, citalopram, duloxetine, escital opram, fluoxetine, levomilnacipran (if locally approved for MDD), milnacipran (if locally approved for MDD), paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine.

[0048] Exclusion criteria include, non-exhaustively: within the patient’s lifetime, a confirmed psychiatric diagnosis other than MDD and in accordance with DSM-5-TR criteria (American Psychiatric Association, The Diagnostic and Statistical Manual of Mental Disorders (5th Ed., text rev.) (2022) (“DSM-5-TR”).), including: schizophrenia,schizoaffective disorder, schizophreniform disorder or other psychotic disorder; Bipolar Disorder; within 6 months, psychiatric diagnosis other than MDD that has been confirmed by DSM-5-TR and that is a primary diagnosis including: Anxiety disorders such as Panic Disorder or Generalized Anxiety Disorder; Obsessive-compulsive Disorder; Posttraumatic Stress Disorder as primary diagnoses (Anxiety symptoms may be allowed if secondary to MDD, provided these symptoms do not require concurrent treatment); Eating disorder; personality disorder of sufficient severity to have a major impact on the patient's psychiatric status; experiencing a > 25% decrease in the MADRS total score between Screening and Baseline; experiencing a > 25% decrease in the QIDS-SR-16 total score between Screening and Baseline; significant risk of suicidal behavior or considered to be in imminent danger to themselves or others; and experiencing a first MDE at age 60 years or older.

[0049] During the baseline visit (Day 0), following confirmation of eligibility, patients are randomized 1 : 1 to either milsaperidone + antidepressant therapy (ADT) or placebo + ADT, stratified by geographic region. Milsaperidone is administered orally using both a bid schedule and qd schedule. The tablet strengths of milsaperidone used in the study are 1 mg, 6 mg, and 12 mg dose strengths. Placebo is administered orally using both a bid schedule and qd schedule. The tablet strengths of the matching placebo used in the study are 1 mg, 6 mg, and 12 mg dose strengths. Table 2 and the flow chart of FIG. 2 may be used to guide treatment assignments.

[0050] The Short-Term Study Treatment Phase consists of two periods: the DoubleBlind Titration Period and the Double-Blind Study Treatment Period. During the 7-day Double-Blind Titration Period, patients continue the ADT they were on at Screening.Patients are not permitted to increase dose of an allowed antidepressant or to switch to a different antidepressant from the screening visit through the end of the Short-Term Phase. If CYP2D6 results are unavailable when the double-blind treatment period dosing is assigned, the patient receives 6 mg bid until their CYP2D6 metabolizer status is determined, after which they switch to their assigned treatment.

[0051] The dosage of study medication (milsaperidone or matching placebo) is gradually increased to 12 mg / day (6 mg bid) for all patients utilizing a fixed titration regimen, whereby the dose is increased from 2 mg / day on day 1 to 4 mg / day on day 2 to 8 mg / day on day 3 to 12 mg / day on day 4 (bid doses of 1, 2, 4 , and 6 mg, respectively) followed by an additional three (3) days of 12 mg / day (given as 6 mg bid) for stabilization on days 5-7.Upon completion of the titration / stabilization period, non-poor CYP2D6 metabolizer patients are given 12 mg of study medication qd in the evening for up to 5 weeks. Poor CYP2D6 metabolizers and patients taking strong CYP2D6 and CYP3 A4 inhibitors (e.g. fluoxetine and paroxetine) will continue to take 12 mg / day of study medication given as 6 mg bid for up to 5 weeks. During this period, patients continue on the ADT they were on at Screening. The Short-Term Study Treatment Phase milsaperidone dosing schedule is summarized in Table 3:Patients are instructed to take medication according to the dosing schedule in Table 3 without regard to meals. Patients are instructed not to chew the medication, but to swallow it whole. Patients following a bid dosing regimen are instructed to take study medication in the morning at approximately 8 a.m. and in the afternoon at approximately 6 p.m. Patients following a qd dosing regimen will be instructed to take study medication in the evening.

[0052] End of phase (EOP) evaluations are performed on Day 42 after the completion of the Double-Blind Short-Term Study Treatment Phase, or upon discontinuation if a patient withdraws prematurely from the study. Patients discontinue study medication after the morning dose on Day 42.

[0053] Based on a two-sided t-test with the 5% significant level, a sample size of 250 subjects per arm (a total of 500 subjects) provides around 92% power to detect a mean difference of 3 points in MADRS (change from baseline at week 6) assuming a standard deviation of 10 in each treatment group. The primary efficacy outcome measure is the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 6. The primary statistical method will be mixed effect model repeat measurement (MMRM). Other secondary efficacy outcomes include CGI-S and CGI-C, which are analyzed similarly to the primary outcome. The categorical endpoints are analyzed by a Cochran-Mantel-Haenszel test with adjusting for sites.

[0054] All patients who complete the Double-Blind Study Treatment Period are eligible to participate in the optional OLE Phase. The purpose of the OLE Phase is to explore the long-term safety of milsaperidone in patients with MDD over an additional 52 weeks. This phase may allow patients previously randomized to the milsaperidone arm in the Short-Term Study Treatment Phase the opportunity to continue on milsaperidone. For patients that were previously randomized to placebo in the Short-Term Study Treatment Phase, this phase may afford them the opportunity to explore the potential benefits of new treatment with adrug not otherwise available to them.

[0055] The Open-Label Extension Phase consists of two treatment periods: an OLE Titration Period followed by an OLE Maintenance Period. The Titration Period lasts for 7 days (Day 43 to Day 49). This period is necessary to transition patients from the Short-Term to the OLE Phase and to equalize all study patients to the maintenance dose of milsaperidone (12 mg / day) without unblinding the Short-Term study data. During the Open-Label Titration Period, all patients, regardless of if they were previously randomized to placebo or milsaperidone, are titrated up to 12 mg / day (6 mg bid) utilizing the same fixed titration regimen as in the Double-Blind Titration Period (see Table 3). The first dose of the OLE Titration Period is the morning of Day 43. During this period, all patients continue the antidepressant therapy (ADT) they were on during the Short-Term Phase.

[0056] Patients then enter the OLE Maintenance Period (Day 50 through Day 385) in which they are treated with milsaperidone + ADT for up to 51 weeks. During the OLE Maintenance Period, non-poor CYP2D6 metabolizer patients are given 12 mg of study medication qd in the evening + ADT. Poor CYP2D6 metabolizers and patients taking strong CYP2D6 and CYP3 A4 inhibitors (e.g. fluoxetine and paroxetine) continue to take 6 mg of study medication bid + ADT. Permission may be granted to increase ADT dosage or switch their antidepressant therapy during the optional Open-Label Extension Phase in certain circumstances.

[0057] While various embodiments are described herein, it will be appreciated from the specification that various combinations of elements, variations or improvements therein may be made by those skilled in the art, and are within the scope of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from essential scope thereof. Therefore, it is intended that the disclosure not be limited to the particular embodiment disclosed, but that the disclosure will include all embodiments falling within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. In a method consisting essentially of treating major depressive disorder (MDD) in a patient in need thereof with an antidepressant, the improvement comprising:administering to the patient an adjunctive treatment comprising an effective dose of milsaperidone.

2. The improvement of claim 1, wherein the effective dose of milsaperidone is 12 mg / day.

3. The improvement of claim 2, wherein the effective dose of milsaperidone is 12 mg / day given as 12 mg qd if and because the patient has a CYP2D6 non-poor metabolizer genotype.

4. The improvement of claim 2, wherein the effective dose of milsaperidone is 12 mg / day given as 6 mg bid if and because the patient has a CYP2D6 poor metabolizer genotype or an unknown CYP2D6 metabolizer genotype.

5. The improvement of claim 2, wherein the effective dose of milsaperidone is 12 mg / day given as 6 mg bid if and because the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3 A4 inhibitor.

6. The improvement of claim 5, wherein the patient is concurrently being administered a CYP2D6 inhibitor selected from the group consisting of:thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine.

7. The improvement of claim 5, wherein the patient is concurrently administered a CYP2D6 inhibitor selected from the group consisting of: fluoxetine and paroxetine.

8. The improvement of claim 5, wherein the patient is being concurrently administered a CYP3A4 inhibitor selected from the group consisting of:Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib,Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafamib, Amprenavir, Amiodarone, and Levoketoconazol e .

9. The improvement of claim 1, wherein the antidepressant is selected from the group consisting of:bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, and vortioxetine.

10. The improvement of claim 1, wherein the improvement results in a superior therapeutic response relative to a therapeutic response achieved or achievable with the method of treating MDD with the antidepressant as a monotherapy.

11. A method of treating major depressive disorder (MDD) in a patient in need thereof, comprising:administering to the patient an effective dose of an antidepressant; and administering to the patient an effective dose of milsaperidone as an adjunctive therapy.

12. The method of claim 11, wherein the effective dose of milsaperidone is 12 mg / day.

13. The method of claim 12, wherein the effective dose of milsaperidone is 12 mg / day given as 12 mg qd if and because the patient has a CYP2D6 non-poor metabolizer genotype.

14. The method of claim 12, wherein the effective dose of milsaperidone is 12 mg / day given as 6 mg bid if and because the patient has a CYP2D6 poor metabolizer genotype or an unknown CYP2D6 metabolizer genotype.

15. The method of claim 12, wherein the effective dose of milsaperidone is 12 mg / day given as 6 mg bid if and because the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3 A4 inhibitor.

16. The method of claim 15, wherein the patient is concurrently administered a CYP2D6 inhibitor selected from the group consisting of:thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine.

17. The method of claim 15, wherein the patient is concurrently administered a CYP2D6 inhibitor selected from the group consisting of: fluoxetine and paroxetine.

18. The method of claim 15, wherein the patient is concurrently administered a CYP3A4 inhibitor selected from the group consisting of:Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole, Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafamib, Amprenavir, Amiodarone, and Levoketoconazol e .

19. The method of claim 11, wherein the antidepressant is selected from the group consisting of:bupropion, citalopram, duloxetine, escitalopram, fluoxetine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, and vortioxetine.

20. A method of initiating adjunctive treatment of major depressive disorder (MDD) with milsaperidone in a patient in need thereof, comprising:administering milsaperidone at a dose of 2 mg / day on day 1;administering milsaperidone at a dose of 4 mg / day on day 2;administering milsaperidone at a dose of 8 mg / day on day 3; andadministering milsaperidone at a dose of 12 mg / day on each of days 4-7.

21. The method of claim 20, wherein:the dose of 2 mg / day on day 1 is given as 1 mg bid;the dose of 4 mg / day on day 2 is given as 2 mg bid;the dose of 8 mg / day on day 3 is given as 4 mg bid; andthe dose of 12 mg / day on each of days 4-7 is given as 6 mg bid.

22. The method of claim 20, further comprising determining whether the patient is a CYP2D6 poor metabolizer by:obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype.

23. The method of claim 22, wherein the patient has a CYP2D6 non-poor metabolizer genotype, and the dose of 12 mg / day on each of days 8 onward is 12 mg qd.

24. The method of claim 22, wherein the patient has a CYP2D6 poor metabolizer genotype, and the dose of 12 mg / day on each of days 8 onward is 6 mg bid.

25. The method of claim 20, wherein the patient is concurrently being administered a CYP2D6 inhibitor or a CYP3A4 inhibitor, and the dose of 12 mg / day on each of days 8 onward is 6 mg bid.

26. The method of claim 25, wherein the patient is concurrently being administered a CYP2D6 inhibitor selected from the group consisting of:thioridazine, cinacalcet, bupropion, methotrimeprazine, fluoxetine, paroxetine, midostaurin, propafenone, glycerol phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, and quinidine.

27. The method of claim 25, wherein the patient is concurrently being administered a CYP2D6 inhibitor selected from the group consisting of: fluoxetine and paroxetine.

28. The method of claim 25, wherein the patient is concurrently being administered a CYP3 A4 inhibitor selected from the group consisting of:Voriconazole, Telithromycin, Ketoconazole, Nefazodone, Itraconazole,Clarithromycin, Saquinavir, Darunavir, Posaconazole, Lopinavir, Telaprevir, Idelalisib, Stiripentol, Curcumin, Ritonavir, Conivaptan, Troleandomycin, Efavirenz, Atazanavir, Tipranavir, Nilotinib, Delavirdine, Ribociclib, Danoprevir, Elvitegravir, Midostaurin, Terfenadine, Ergotamine, Econazole, Ditiocarb, Indinavir, Nelfinavir, Methimazole, Boceprevir, Danazol, Diltiazem, Lonafamib, Amprenavir, Amiodarone, and Levoketoconazol e .

29. The method of claim 20, wherein the patient is stabilized on treatment with an antidepressant prior to initiating the adjunctive treatment.

30. The method of claim 29, wherein initiating the adjunctive treatment results in an improved therapeutic response relative to a therapeutic response achieved or achievable with treatment of the MDD with the antidepressant as a monotherapy.

31. Milsaperidone for use in the treatment of maj or depressive disorder (MDD) in a patient in need thereof, the treatment comprising:administration to the patient of an effective dose of milsaperidone, wherein the milsaperidone is as an adjunctive therapy to treatment with an effective dose of an antidepressant.

32. Use of milsaperidone for the manufacture of a medicament for use in the treatment of major depressive disorder (MDD) in a patient in need thereof, the treatment comprising: administration to the patient of an effective dose of milsaperidone, wherein the milsaperidone is as an adjunctive therapy to treatment with an effective dose of an antidepressant.

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