WO2016123543A1 - Procédé de traitement de la schizophrénie comprenant l'administration de lurasidone - Google Patents

Procédé de traitement de la schizophrénie comprenant l'administration de lurasidone Download PDF

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WO2016123543A1
WO2016123543A1 PCT/US2016/015760 US2016015760W WO2016123543A1 WO 2016123543 A1 WO2016123543 A1 WO 2016123543A1 US 2016015760 W US2016015760 W US 2016015760W WO 2016123543 A1 WO2016123543 A1 WO 2016123543A1
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variant
positive
intergenic
individual
tnfrsfib
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PCT/US2016/015760
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Jarlath Ffrench-Mullen
Eric Lai
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Takeda Pharmaceuticals U.S.A., Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to methods and kits for treating schizophrenia in an individual, and for identifying the likelihood that an individual suffering from schizophrenia will respond favorably to treatment with lurasidone and/or experience an enhanced treatment effect when treated with lurasidone.
  • These methods and kits are based on detecting the presence of polymorphisms in the Tumor necrosis factor receptor superfamily member IB (TNFRSF1B) gene and/or the Disks large-associated protein 1 (DLGAP1) gene and/or intergenic regions.
  • TNFRSF1B Tumor necrosis factor receptor superfamily member IB
  • DSGAP1 Disks large-associated protein 1
  • Schizophrenia is a brain disorder in which individuals interpret reality abnormally and may result in hallucinations, delusions, disorganized thinking (speech), disordered or abnormal motor behavior, and negative symptoms (e.g., social withdrawal, lack of emotion, and so forth). Schizophrenia is a chronic condition requiring lifelong treatment that often starts in men in the early to mid-20s while for women, symptoms typically begin in the late 20s. The cause of schizophrenia is unknown, but it is believed that a combination of genetics and environment contribute to the development of this disorder. If left untreated, schizophrenia can result in severe emotional, behavioral, and health problems affecting many aspects of everyday life. For example, complications associated with schizophrenia include suicide, anxiety, abuse of alcohol, drugs, or prescription medications, poverty, homelessness, inability to work, social isolation, and so forth.
  • Antipsychotics are available for the treatment of schizophrenia.
  • Antipsychotics may include conventional or typical antipsychotics that are often associated with neurological side effects.
  • Antipsychotics may also include atypical antipsychotics, which often pose a lower risk of side effects than typical antipsychotics.
  • individual response to antipsychotics is suboptimal and variable. That is, not all individuals respond equally to a given antipsychotic. Accordingly, many patients do not receive adequate treatment of schizophrenia and many respond partially or not at all to treatment.
  • Lurasidone is one atypical antipsychotic indicated for the treatment of schizophrenia. Lurasidone is also indicated for the treatment of bipolar disorder.
  • Lurasidone is known to be an antagonist of dopamine D2 receptors and 5-hydroxytryptamine (5-HT or serotonin) receptors 5-HT2A and 5-HT7. Lurasidone also has other activities such as being a partial agonist at serotonin 5-HT1 A receptors and an antagonist at a2A adrenergic receptors.
  • antipsychotic medication such as lurasidone.
  • One aspect of the invention provides a method for treating schizophrenia in an individual, the method comprising administering lurasidone to an individual identified as (i) TNFRSF1B variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSF1B variant positive and DLGAPl variant positive, (v) TNFRSF1B variant positive and intergenic variant positive, (vi) DLGAPl variant positive and intergenic variant positive, or (vii) TNFRSF1B variant positive, DLGAPl variant positive, and intergenic variant positive, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position
  • Another aspect of the invention provides a method for determining the likelihood that an individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone, the method comprising: obtaining a biological sample from the individual; assaying the sample for the presence or absence of a TNFRSF1B variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual; and determining if the individual is likely to experience an enhanced treatment effect as compared to an individual who has been treated with a placebo when the TNFRSF1B variant and/or the DLGAPl variant and/or the intergenic variant are detected in the sample, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Another aspect of the invention provides a method for treating schizophrenia in an individual identified as (i) TNFRSFIB variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSFIB variant positive and DLGAPl variant positive, (v) TNFRSFIB variant positive and intergenic variant positive, (vi) DLGAPl variant positive and intergenic variant positive, or (vii) TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive, the method comprising administering lurasidone to the individual, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Another aspect of the invention provides a method for determining the likelihood that a first individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone as compared to a second individual who has been treated with a placebo, the method comprising: obtaining a biological sample from the first individual; assaying the sample to determine the presence or absence of a TNFRSFIB variant and/or a DLGAPl variant and/or intergenic variant in nucleic acids from the first individual; and determining the first individual is likely to experience an enhanced treatment effect when treated with lurasidone if (i) a TNFRSFIB variant positive, (ii) a DLGAPl variant positive, (iii) a intergenic variant positive, (iv) a TNFRSFIB variant positive and a DLGAPl variant positive, (v) a TNFRSFIB variant positive and a intergenic variant positive, (vi) a DLGAPl variant positive and a intergenic variant positive, or (vii) a TNFRSFIB variant positive
  • Another aspect of the invention provides a method for determining the likelihood that an individual suffering from schizophrenia will respond favorably to treatment with lurasidone, the method comprising: obtaining a biological sample from the individual; assaying the sample from the individual to determine the presence of a TNFRSFIB variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual; and determining the individual is likely to respond favorably to treatment with lurasidone when the individual is (i) TNFRSFIB variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSFIB variant positive and DLGAPl variant positive, (v) TNFRSFIB variant positive and intergenic variant positive, (vi) DLGAPl variant positive and intergenic variant positive, or (vi) TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position
  • Another aspect of the invention provides a method of determining the likelihood that a first individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone as compared to a second individual who has been treated with a placebo, the method comprising the steps of: (a) assaying in a sample obtained from the first individual for the presence or absence of a TNFRSFIB variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the first individual; (b) assigning a first value to the presence or absence of the TNFRSFIB variant, a second value to the presence or absence of the DLGAPl variant, and/or a third value to the presence or absence of the intergenic variant in nucleic acids from the first individual; (c) combining the first value, second value, and third value in step b to obtain a total score for the first individual; (d) comparing the total score determined in step c with a predetermined total score; and (e) determining if the first individual is likely to experience
  • kits comprising a primer pair for detecting a TNFRSFIB variant and/or a primer pair for detecting a DLGAPl variant and/or a primer pair for detecting an intergenic variant in nucleic acids from an individual, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • FIG. 1 shows a summary of the genotypic Quality Control (QC) procedures of the IlluminaTM HumanOmni5EXOME whole genome bead-chip array dataset.
  • FIG. 2 shows a graph plotting single nucleotide polymorphism vs. estimated response probability for marker refinement.
  • FIG. 3 shows a graph plotting combined treatment arms vs. estimated change in PANSS in the 6 SNP model.
  • FIG. 4 shows a graph plotting combined treatment arms vs. predicted response rate in PANSS in the 6 SNP model.
  • FIG. 5 shows a graph plotting dosage vs. estimated change in PANSS in the 6 SNP model.
  • FIG. 6 shows a graph plotting combined treatment arms vs. estimated change in PANSS in the 3 SNP model.
  • FIG. 7 shows a graph plotting combined treatment arms vs. predicted response rate in PANSS in the 3 SNP model.
  • FIG. 8 shows a graph plotting dosage vs. estimated change in PANSS in the 3 SNP model.
  • FIG. 9 shows a graph plotting combined treatment arms and Olanzapine (60 mg) vs. estimated change in PANSS in the 6 SNP model.
  • FIG. 10 shows a graph plotting combined treatment arms and Olanzapine vs. predicted response rate in PANSS in the 6 SNP model.
  • FIG. 11 shows a graph plotting combined treatment arms and Olanzapine vs. estimated change in PANSS in the 3 SNP model.
  • FIG 12 shows a graph plotting combined treatment arms and Olanzapine vs. predicted response rate in PANSS in the 3 SNP model.
  • FIG. 13 shows a graph of the combined treatment arms for the clinical PANSS change from baseline.
  • FIG. 14 shows a graph illustrating the change of the clinical PANSS from baseline for 40 mg Lurasidone with the 6-SNP biomarker (BM) positive (BMpos) and negative (BMneg).
  • FIG. 15 shows a graph illustrating the change of the clinical PANSS from baseline for 80 mg Lurasidone with the 6-SNP biomarker (BM) positive (BMpos) and negative (BMneg).
  • FIG. 16 shows a graph illustrating the change of the clinical PANSS from baseline for 120 mg Lurasidone with the 6-SNP biomarker (BM) positive (BMpos) and negative (BMneg).
  • FIG. 17 shows a graph illustrating the change of the clinical PANSS from baseline for 40 mg Lurasidone with the 3-SNP biomarker (BM) positive (BMpos) and negative (BMneg).
  • FIG. 18 shows a graph illustrating the change of the clinical PANSS from baseline for 80 mg Lurasidone with the 3-SNP biomarker (BM) positive (BMpos) and negative (BMneg).
  • FIG. 19 shows a graph illustrating the change of the clinical PANSS from baseline for 120 mg Lurasidone with the 3-S P biomarker (BM) positive (BMpos) and negative (BMneg).
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • DLGAPF refers to Disks large-associated protein 1.
  • DLGAP1 may also be known as GKAP.
  • DLGAPl variant refers to a DLGAP1 gene with a sequence that is less than 100% identical to that of NCBI Gene Identification number 9229.
  • the DLGAP1 variant exhibits at least one polymorphism as compared to a wild type DLGAP1 gene.
  • enhanced treatment response refers to an individual who experiences a greater improvement in schizophrenia symptoms when treated with a drug such as lurasidone than an individual suffering from schizophrenia and who has been treated, but is not positive for a TNFRSF1B variant, and/or a DLGAP1 variant, and/or an intergenic variant (such as rs 10512247), as described herein.
  • identity in the context of two or more polypeptide or polynucleotide sequences, can mean that the sequences have a specified percentage of residues that are the same over a specified region. The percentage can be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity. In cases where the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of the single sequence are included in the denominator but not the numerator of the calculation.
  • intergenic region refers to a region between two genes.
  • intergenic variant is a region between two genes that exhibits at least one polymorphism as compared to a wild type intergenic region.
  • isolated nucleic acids denotes nucleic acids that are removed to at least some extent from the cellular material from which they originated. However, “isolated” does not require that the nucleic acids are completely pure and free of any other components. Examples of isolated nucleic acids are those obtained using commercial nucleic acid extraction kits.
  • “lurasidone” refers to (3aR,4S,7R,7aS)-2-[((lR,2R)-2- ⁇ [4-(l,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl ⁇ cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione.
  • the term “lurasidone” may refer to the free base form of lurasidone, an acid addition salt thereof, such as lurasidone hydrochloride, and any other pharmaceutically acceptable salts of lurasidone.
  • Mir4632 refers to a microRNA that is encoded by a sequence located within the TNFRSF1B gene.
  • the sequence encoding Mir4632 may be located after the second exon of the TNFRSF1B gene.
  • subject As used herein, "subject,” “individual” and “patient” interchangeably refer to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.) and a human).
  • a mammal e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse
  • a non-human primate for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.
  • the subject may be a human or a non-human.
  • TNFRSF1B refers to tumor necrosis factor receptor superfamily member IB. TNFRSF1B may also be known as TNF-R2 or TNF-RII.
  • TNFRSF1B variant refers to a TNFRSF1B gene with a sequence that is less than 100% identical to that of NCBI Gene Identification number 7133. In some embodiments, the TNFRSF1B variant exhibits at least one polymorphism as compared to a wild type TNFRSF1B gene.
  • TNFRSF1B variant positive refers to an individual who is heterozygous or homozygous for a TNFRSF1B variant.
  • the terms “treat,” “treating,” or “treatment” interchangeably mean to reverse, alleviate, or inhibit the progress of a disease, or one or more symptoms of such disease, to which such term applies.
  • the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing symptoms associated with a disease.
  • a treatment may be either performed in an acute or chronic way.
  • the term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease.
  • Preventing also refers to preventing the recurrence of a disease with one or more symptoms associated with such disease.
  • Treatment and
  • sample may be any substance obtained from an individual wherein the substance contains nucleic acids from the individual.
  • sample types include a body fluid sample, a tissue sample, a stool sample, cells from the individual, and isolated nucleic acids obtained from the individual.
  • body fluid samples include blood, plasma, serum, cerebrospinal fluid, and saliva.
  • tissue samples include tissue biopsy samples.
  • Exemplary cell samples include buccal swabs or cells obtained from any biological samples taken from the individual.
  • a sample from an individual contains DNA and/or RNA from the individual.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • the method comprises administering lurasidone to an individual identified as (i) TNFRSF1B variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSF1B variant positive and DLGAPl variant positive, (v) TNFRSF1B variant positive and intergenic variant positive; (vi) DLGAPl variant positive and intergenic variant positive; or (vii) TNFRSF1B variant positive, DLGAPl variant positive, and intergenic variant positive.
  • the method treats schizophrenia in an individual identified as (i) TNFRSF1B variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSF1B variant positive and DLGAPl variant positive, (v) TNFRSF1B variant positive and intergenic variant positive; (vi) DLGAPl variant positive and intergenic variant positive; or (vii) TNFRSF1B variant positive, DLGAPl variant positive, and intergenic variant positive as provided herein and comprises administering lurasidone to the individual.
  • the method comprises determining whether an individual is (i) TNFRSF1B variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSF1B variant positive and DLGAPl variant positive, (v) TNFRSF1B variant positive and intergenic variant positive; (vi) DLGAPl variant positive and intergenic variant positive; or (vii) TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive and administering lurasidone to the individual.
  • Lurasidone may be administered or ingested in a tablet form.
  • the tablet form may contain, for example, lurasidone HCl ((3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2-[4-(l,2-benzisothiazol-3- yl)piperazin-lylmethyl] cyclohexylmethyl ⁇ hexahydro-4,7-methano-2H-isoindole-l,3-dione hydrochloride) having the structural formula:
  • lurasidone may be administered to a patient or ingested at a dose of in an amount of about 1 mg/day to about 750 mg/day, about 1 mg/day to about 700 mg/day, about 1 mg/day to about 650 mg/day, about 1 mg/day to about 600 mg/day, about 1 mg/day to about 550 mg/day, about 1 mg/day to about 500 mg/day, about 1 mg/day to about 450 mg/day, about 1 mg/day to about 400 mg/day, about 1 mg/day to about 350 mg/day, about 1 mg/day to about 300 mg/day, about 1 mg/day to about 250 mg/day, about 1 mg/day to about 200 mg/day, about 1 mg/day to about 180 mg/day, about 1 mg/day to about 150 mg/day, about 1 mg/day to about 100 mg/day, about 1 mg/day to about 50 mg/day, about 5 mg/day to about 750 mg/day, about 5 mg/day to about 700 mg/
  • lurasidone may be administered or ingested at a dose of about 1 mg/day, about 5 mg/day, about 10 mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, or about 750 mg/day inclusive of any single or multi-dose daily administration regimen that falls within that total daily dose range.
  • the dose is from about 20 mg/day to about 180 mg/day.
  • lurasidone is administered or ingested at a dose of about 1 mg/day,
  • Treatment may continue for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 3 months, at least 4 months, least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or at least 18 months.
  • the present inventors surprisingly discovered that individuals suffering from schizophrenia who possess a TNFRSFIB variant, a DLGAPl variant, and/or an intergenic variant are more likely to experience an enhanced treatment response to lurasidone than individuals who do not possess a TNFRSFIB variant positive, a DLGAPl variant, and/or an intergenic variant.
  • individuals with this genotype are likely to respond favorably to treatment with lurasidone, meaning, the individual is at least 1.22 or 1.37 times more likely to respond to lurasidone treatment as compared to an individual that is treated with a placebo.
  • individuals with this genotype are likely to response favorably to treatment with lurasidone, meaning, the individual is at least 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 times more likely to respond to lurasidone treatment as compared to the individual that is treated with a placebo.
  • an individual suffering from schizophrenia who possesses a TNFRSF1B variant is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess a TNFRSF1B variant.
  • TNFRSF1B may refer to the tumor necrosis factor receptor superfamily member IB, which is located on chromosome 1 at lp36.2. The transcription start and stop positions are located at 12, 167,003 and 12,209,228, respectively.
  • An exemplary nucleotide sequence of the TNFRSF1B gene is that of NCBI Reference Sequence accession number 7133, the sequence of which is incorporated by reference herein.
  • the TNFRSF1B variant may be rs 1061628, rs522807, rs496888, rsl7879121, rs542282, rsl815530, or combinations thereof. In other embodiments, the
  • TNFRSF1B variant may be rs 1061628.
  • the TNFRSF1B variant may be a combination of rsl061628, rs522807, rs496888, and rsl7879121.
  • the TNFRSFIB variant may be a combination of rsl061628, rs522807, rs496888, rsl7879121, rs542282, and rsl815530.
  • the TNFRSFIB variant may be a S P found within MIR4632 which is also found within TNFRSFIB, such as rsl815530, which is a SNP found within MIR4632, which is within TNFRSFIB.
  • the major allele (A) and minor allele (B) for each TNFRSFIB variant is shown in Table 1.
  • an individual suffering from schizophrenia who possesses a DLGAPl variant is more likely to experience an enhanced treatment response to lurasidone than the individual who does not possess a DLGAPl variant.
  • DLGAPl may refer to disks large-associated protein 1, which is located on chromosome 18 at 18pl 1.31. The transcription start and stop positions are located at 3,496,032 and 4,455,335, respectively.
  • An exemplary nucleotide sequence of the DLGAPl gene is that of NCBI Reference Sequence accession number 9229, the sequence of which is incorporated by reference herein.
  • the DLGAPl variant may be rsl442377.
  • rsl442377 is located in the intron of DLGAPl gene at position 4,056, 108 on chromosome 18.
  • the major allele (A) is C while the minor allele (B) is T.
  • an individual suffering from schizophrenia who possesses an intergenic variant is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess an intergenic variant.
  • the intergenic variant is associated with a favorable response to lurasidone.
  • the intergenic variant may be located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9. In other embodiments, the intergenic variant may be located from position 95,934, 046 on chromosome 9 to position 95,934, 221 on chromosome 9, from position 95,934, 071 on chromosome 9 to position
  • the intergenic variant may be rsl0512247.
  • rsl0512247 is located at position 95,934,121 on chromosome 9.
  • the major allele (A) is G while the minor allele (B) is A.
  • the global minor allele frequency (MAF) for rsl0512247 is 0.0513.
  • An individual suffering from schizophrenia who possesses any combination of the above described TNFRSFIB variant, DLGAPl variant, and intergenic variant is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess this combination(s).
  • an individual suffering from schizophrenia who possesses (i) a TNFRSFIB variant, (ii) a, DLGAPl variant, (iii) an intergenic variant (such as rs 10512247, ) , (iv) a TNFRSFIB variant and a DLGAPl variant, (v) a TNFRSFIB variant and an intergenic variant (such as rsl0512247), (vi) a, DLGAPl variant and an intergenic variant (such as rsl0512247), or (vii) a TNFRSFIB variant, a, DLGAPl variant, and an intergenic variant (such as rsl0512247 , is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess (i) the TNFRSFIB variant, (ii) the DLGAPl variant, (iii) the intergenic variant, (iv) the TNFRSFIB variant and the DLGAPl variant, (
  • the TNFRSFIB variant may be rsl061628, rs522807, rs496888, rsl7879121, rs542282, rsl815530, and combinations thereof.
  • the DLGAPl variant may be rsl442377.
  • the intergenic variant may be rsl0512247.
  • an individual suffering from schizophrenia who possesses a TNFRSFIB variant, a DLGAPl variant, and an intergenic variant is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess the
  • TNFRSFIB variant the DLGAPl variant, and the intergenic variant.
  • an individual suffering from schizophrenia who possesses rsl061628, rsl0512247, and rsl442377 is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess rsl061628, rsl0512247, and rsl442377.
  • an individual suffering from schizophrenia who possesses rsl061628, rs522807, rs496888, rsl7879121, rsl0512247, and rsl442377 is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess rsl061628, rs522807, rs496888, rsl7879121, rsl0512247, and rsl442377.
  • an individual suffering from schizophrenia who possesses rsl061628, rs522807, rs496888, rsl7879121, rsl0512247, rsl442377, rs542282, and rsl815530 is more likely to experience an enhanced treatment response to lurasidone than an individual who does not possess rsl061628, rs522807, rs496888, rsl7879121, rsl0512247, rsl442377, rs542282, and rsl815530.
  • an individual who suffers from schizophrenia is an individual who meets the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for schizophrenia.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • Psychopathology symptoms of schizophrenia and the degree of improvement with treatment are assessed using standard schizophrenia rating scales such as the Positive and Negative Syndrome Scale (PANSS).
  • PANSS Positive and Negative Syndrome Scale
  • This scale consists of 30 items arranged as 7 positive symptom items, 7 negative symptom items, and 16 general symptom items. Each item is rated on a 7-point scale, i.e., 1 (absent) to 7 (extreme). The rating is based on a clinical interview with the patient and the gathering of informant information, and allows for a precise rating of severity. Total score is from 30 to 210, with a higher score being the more severe.
  • Treatment efficacy is determined based on an improvement in one or more schizophrenia symptoms as measured by mean change in PANSS score.
  • the individual has a total PANSS score of greater than or equal to about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 60 to about 120, about 70 to about 120, about 80 to about 120, about 60 to about 110, about 70 to about 100, about 80 to about 90, or a greater than or equal to about 10, a greater than or equal to about 20, a greater than or equal to about 30, a greater than or equal to about 40, a greater than or equal to about 50, a greater than or equal to about 60, a greater than or equal to about 70, a greater than or equal to about 80, a greater than or equal to about 90, or a greater than or equal to about 100 prior to treatment.
  • the individual has a total PANSS score of greater than or equal to 80 prior to treatment.
  • the method comprises assaying a sample from the individual suffering from schizophrenia to determine the presence or absence of the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant in nucleic acids from the individual.
  • the individual is determined to be likely to experience an enhanced treatment effect when treated with lurasidone if the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant are present in the nucleic acids from the individual.
  • the step of assaying the sample is described below in more detail.
  • the method may further comprise assigning a first value to the presence or absence of the TNFRSF1B variant, a second value to the presence or absence of the DLGAP1 variant, and/or a third value to the presence or absence of the intergenic variant (such as rsl0512247) in nucleic acids from the individual.
  • This method may include combining (i.e., adding together) the first value, second value, and third value to obtain a total score for said individual, comparing the total score with a predetermined total score, and determining if the individual is likely to experience an enhanced treatment effect when treated with lurasidone based on this comparison.
  • the first value, second value, and third value may be a product of a S P coefficient and a SNP G value.
  • the G value is predetermined for a particular allele. For example, a particular allele present may be assigned a G value of 0, 1, or 2.
  • the first value may be a product of a rs 1061628 coefficient and rs 1061628 G value.
  • the first value may be a combination of (a) a product of a rs 1061628 coefficient and rs 1061628 G value; (b) a product of a rs522807 coefficient and rs52280 G value 7; (c) a product of a rs496888 coefficient and rs496888 G value; and (d) a product of a rsl7879121 coefficient and rsl7879121 G value.
  • the second value may be a product of a rs 1442377 coefficient and rs 1442377 G value.
  • the third value may be a product of a rs 10512247 coefficient and rs 10512247 G value.
  • the total score obtained for the individual may be compared with the predetermined total score.
  • the predetermined total score may be employed as a benchmark against which to assess the results obtained upon assaying the sample for particular variants (e.g., SNPs) and determining the total score.
  • the predetermined total score may be chosen from amongst the possible total scores an individual may have, in which each possible total score may define a respective subgroup of individuals with greater total scores.
  • the predetermined total score may be chosen such the corresponding subgroup maximizes the association between treatment by subgroup interaction and an outcome of interest (e.g., PANSS change from baseline and response rate).
  • the method comprises assaying a sample from the individual to determine the presence of the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant in nucleic acids from the individual, and determining that the individual is likely to respond favorably to treatment with lurasidone when the individual is TNFRSFIB variant positive and/or the DLGAPl variant positive and/or the intergenic variant positive.
  • the step of assaying the sample is described below in more detail.
  • the method may further comprise administering lurasidone to the TNFRSFIB variant positive and/or the DLGAPl variant positive and/or the intergenic variant positive individual.
  • the methods of determining the enhanced treatment effect and predicting the response to lurasidone include a step of assaying the sample.
  • Assaying the sample may include detecting the TNFRSFIB variant and/or the DLGAPl variant and/or the intergenic variant in the sample.
  • TNFRSFIB variant and/or the DLGAPl variant and/or the intergenic variant may use a labeled oligonucleotide.
  • assaying the sample may involve extracting nucleic acids from the sample.
  • the nucleic acids may include DNA, RNA, or both DNA and RNA.
  • RNA extraction is not essential and a sample such as, for example, blood or saliva may be assayed directly without extracting nucleic acids from the sample. a) Amplification
  • assaying the sample may comprise reverse transcribing RNA to produce cDNA, which in turn, may be amplified to produce an amplicon.
  • assaying the sample may comprise amplifying DNA (e.g., genomic DNA) to produce the amplicon.
  • the amplicon may contain a particular variant (e.g., SNP) within its nucleic acid sequence. Amplifying may mean generating and increasing the number of copies of the amplicon.
  • the amplicon may have various lengths or different sizes as long as the SNP is within the nucleic acid sequence of the amplicon.
  • assaying the sample may comprise amplifying nucleic acids in the sample or nucleic acids derived from nucleic acids in the sample (e.g. cDNA). Accordingly, the methods described herein may incorporate a step of amplifying the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant. The TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant may be amplified and then detected.
  • Nucleic acid amplification techniques may include cloning, PCR, allele specific PCR (ASA), ligase chain reaction (LCR), nested polymerase chain reaction, self-sustained sequence replication, transcriptional amplification system, and Q-Beta Replicase, as described in Kwoh, D. Y. et al., 1988, Bio/Technology 6: 1197, which is incorporated herein by reference.
  • ASA allele specific PCR
  • LCR ligase chain reaction
  • nested polymerase chain reaction self-sustained sequence replication
  • transcriptional amplification system and Q-Beta Replicase
  • Amplification methods which may be used include variations of RT-PCR, including quantitative RT-PCR, for example, as adapted to the method described by Wang, A. M. et al., Proc. Natl. Acad. Sci. USA 86:9717-9721, (1989), or by Karet, F. E., et al., Analytical Biochemistry
  • ASPCR allele specific PCR
  • Amplification products may be assayed by size analysis, restriction digestion followed by size analysis, detecting specific tagged oligonucleotide primers in reaction products, allele-specific oligonucleotide (ASO) hybridization, allele specific 5' exonuclease detection, sequencing, and/or hybridization.
  • Nucleic acid primers and/or oligonucleotides may be used in conjunction with any of the herein described methods and/or kits.
  • the oligonucleotide may be synthesized and selected to hybridize to an amplified product (e.g., amplicon).
  • the oligonucleotide may comprise a detectable label.
  • PCR-based detection methods may include amplification of a single variant (e.g., SNP) or a plurality of variants simultaneously.
  • PCR primers may be synthesized and selected to generate PCR products (e.g., amplicons) that do not overlap in size and may be analyzed simultaneously.
  • PCR products e.g., amplicons
  • one may amplify different variants with primers that are differentially labeled. Each variant may then be differentially detected.
  • Hybridization-based detection methods may allow the differential detection of multiple PCR products in a sample.
  • Another method of assaying the sample to determine the presence of a genetic variant comprises nucleic acid sequencing. Sequencing can be performed using any number of methods, kits or systems known in the art. One example is using dye terminator chemistry and an ABI sequencer (Applied Biosystems, Foster City, Calif). Sequencing also may involve single base determination methods such as single nucleotide primer extension ("SNapShot® " sequencing method) or allele or mutation specific PCR.
  • SNaPshot® Multiplex System is a primer extension-based method that enables multiplexing up to 10 SNPs (single nucleotide
  • the chemistry is based on the dideoxy single-base extension of an unlabeled oligonucleotide primer (or primers). Each primer binds to a complementary template in the presence of fluorescently labeled ddNTPs and AmpliTaq® DNA Polymerase, FS. The polymerase extends the primer by one nucleotide, adding a single ddNTP to its 3' end.
  • SNaPshot® Multiplex System is commercially available (ABI PRISM. SNaPshot® Multiplex kit, Applied Biosystems Foster City, Calif). Products generated using the ABI PRISM®
  • SNaPshot® Multiplex kit can be analyzed with GeneScan® Analysis Software version 3.1 or higher using ABI PRISM® 310 Genetic Analyzer, ABI PRISM® 3100 Genetic Analyzer or ABI PRISM® 3700 DNA Analyzer. c) Next Generation Sequencing
  • Next generation sequencing also may be used to determine an individual's genotype.
  • Next generation sequencing is a high throughput, massively parallel sequencing method that can generate multiple sequencing reactions of clonally amplified molecules and of single nucleic acid molecules in parallel. This allows increased throughput and yield of data.
  • NGS methods include, for example, sequencing-by-synthesis using reversible dye terminators, and sequencing-by-ligation.
  • Non-limiting examples of commonly used NGS platforms include miRNA BeadArray (Illumina, Inc.), Roche 454TM GS FLXTM-Titanium (Roche Diagnostics), XMAP® (Luminex Corp.), IONTORRENTTM (Life Technologies Corp.) and ABI SOLiDTM System (Applied Biosystems, Foster City, CA).
  • assaying the sample may comprise large scale SNP genotyping.
  • Large scale SNP genotyping may include any of dynamic allele-specific hybridization (DASH), microplate array diagonal gel electrophoresis (MADGE), pyrosequencing, oligonucleotide- specific ligation, or various DNA "chip” technologies such as Affymetrix SNP chips. These methods may require amplification of the target genetic region. Amplification may be accomplished via polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant may be detected using a specialized exonuclease-resistant nucleotide, as described in U.S. Pat. No. 4,656,127, which is incorporated herein by reference.
  • a primer complementary to the allelic sequence immediately 3' to the polymorphic site may be permitted to hybridize to a target molecule obtained from the subject. If the polymorphic site on the target molecule contains a nucleotide that is complementary to the particular exonuclease-resistant nucleotide derivative present, then that derivative may be incorporated onto the end of the hybridized primer. Such incorporation may render the primer resistant to exonuclease, and thereby permit its detection.
  • a solution-based method may be used to determine the identity of the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant, as described in PCT
  • a primer may be employed that is complementary to allelic sequences immediately 3' to a polymorphic site.
  • the method may determine the identity of the nucleotide of that site using labeled dideoxy nucleotide derivatives that, if complementary to the nucleotide of the polymorphic site, will become incorporated onto the terminus of the primer.
  • assaying the sample may comprise genetic bit analysis.
  • Genetic bit analysis may use mixtures of labeled terminators and a primer that is complementary to the sequence 3' to a polymorphic site.
  • a labeled terminator may be incorporated, wherein it is determined by and complementary to, the nucleotide present in the polymorphic site of the target molecule being evaluated.
  • the primer or the target molecule may be immobilized to a solid phase.
  • a primer-guided nucleotide incorporation procedure may be used to assay for the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant in a nucleic acid, as described in Nyren, P. et al., Anal. Biochem. 208: 171-175 (1993), which is herein incorporated by reference.
  • Such a procedure may rely on the incorporation of labeled deoxynucleotides to discriminate between bases at a polymorphic site.
  • the signal is proportional to the number of deoxynucleotides incorporated, thus polymorphisms that occur in runs of the same nucleotide may result in signals that are proportional to the length of the run.
  • Allele specific hybridization may be used to detect the TNFRSF1B variant and/or the DLGAP1 variant and/or the intergenic variant.
  • This method may use a probe capable of hybridizing to a target allele.
  • the probe may be labeled.
  • a probe may be an oligonucleotide.
  • the target allele may have between 3 and 50 nucleotides around the variant.
  • the target allele may have between 5 and 50, between 10 and 40, between 15 and 40, or between 20 and 30 nucleotides around the variant.
  • a probe may be attached to a solid phase support, e.g., a chip.
  • Oligonucleotides may be bound to a solid support by a variety of processes, including lithography.
  • a chip may comprise more than one allelic variant of a target region of a nucleic acid, e.g., allelic variants of two or more polymorphic regions of a gene.
  • Examples of other techniques for detecting alleles include selective oligonucleotide hybridization, selective amplification, or selective primer extension.
  • Oligonucleotide primers may be prepared in which the known mutation or nucleotide difference is placed centrally and then hybridized to target DNA under conditions which permit hybridization if a perfect match is found.
  • Such allele specific oligonucleotide hybridization techniques may be used to test one mutation or polymorphic region per reaction when oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations or polymorphic regions when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.
  • Allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention.
  • Oligonucleotides used as primers for specific amplification may carry the mutation or polymorphic region of interest in the center of the molecule. Amplification may then depend on differential hybridization, as described in Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448), which is herein incorporated by reference, or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension.
  • Direct DNA sequencing may detect sequence variation.
  • Another approach is the single-stranded conformation polymorphism assay (SSCP), as described in Orita M, et al. (1989) Proc. Natl. Acad. Sci. USA 86:2766-2770, which is incorporated herein by reference.
  • the fragments that have shifted mobility on SSCP gels may be sequenced to determine the exact nature of the DNA sequence variation.
  • Other approaches based on the detection of mismatches between the two complementary DNA strands include clamped denaturing gel electrophoresis (CDGE), as described in Sheffield V C, et al. (1991) Am. J. Hum. Genet.
  • CDGE clamped denaturing gel electrophoresis
  • an allele specific detection approach such as allele specific oligonucleotide (ASO) hybridization can be utilized to rapidly screen large numbers of other samples for that same mutation.
  • ASO allele specific oligonucleotide
  • Such a technique can utilize probes that may be labeled with gold nanoparticles to yield a visual color result as described in Elghanian R, et al. (1997) Science 277: 1078-1081, which is herein incorporated by reference.
  • a rapid preliminary analysis to detect polymorphisms in DNA sequences can be performed by looking at a series of Southern blots of DNA cut with one or more restriction enzymes, preferably with a large number of restriction enzymes.
  • kits for detecting a TNFRSF1B variant and/or a DLGAP1 variant and/or an intergenic variant (such as rsl0512247) in nucleic acids from an individual may comprise a primer pair for detecting a TNFRSF1B variant and/or a primer pair for detecting a DLGAP1 variant and/or a primer pair for detecting an intergenic variant (such as rsl0512247) in nucleic acids from an individual.
  • the kit may comprise a probe for detecting a TNFRSF1B variant and/or a probe for detecting a DLGAPl variant and/or a probe for detecting an intergenic variant (such as rsl0512247) in nucleic acids from an individual.
  • the kit may also include a positive control and/or a negative control.
  • the kit may include material(s), which may be desirable from a user standpoint, such as a buffer(s), a diluent(s), a standard(s), and/or other material useful in sample processing, washing, or conducting any other step of the methods described herein.
  • the kit according to the present disclosure may also include instructions for carrying out the methods of the invention. Instructions included in the kit of the present disclosure may be affixed to packaging material or may be included as a package insert. While instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term "instructions" can include the address of an internet site which provides instructions.
  • the present invention has multiple aspects, illustrated by the following non-limiting examples.
  • Study design treatment groups . Multi center, randomized, double-blind, parallel- group, placebo-controlled drug-referenced, fixed dose studies were conducted to evaluate the efficacy and safety of lurasidone (40, 80, and 120 mg/Day) in the acute treatment of adult patients with Schizophrenia. A total of 670 individuals meeting the diagnostic criteria from the DSV-IV-TR for Schizophrenia were included in the studies. See Tables 5 and 6. Specifically, these 670 individuals were from study 229 and study 231 and the analysis described herein in Examples 1, 2, and 3 was with respect to the combination of studies 229 and 231. Studies 229 and 231 were also analyzed separately as described below in Example 4. [00113] Individuals were treated with 40, 80, or 120 mg lurasidone, or a different drug, or a placebo daily for 6 weeks. See Tables 5 and 6.
  • the primary outcome measure was change from baseline in PANSS total score after 6 weeks. For this continuous endpoint, a linear regression model was built.
  • Secondary outcome measures included the proportion of responders at week 6.
  • responders were defined as a 30% or greater improvement in PANSS total score, i.e., a decreased PANSS total score, from baseline ("Response def 1").
  • responders were defined as a 50% or greater improvement in PANSS score,
  • Study design genotype determination. Nucleic acid samples from the individuals were run on an IlluminaTM HumanOmni5EXOME whole genome bead-chip array according to the manufacturer's protocol. 976 samples were genotyped for 4,641,218 variants. 670 of the 976 samples were considered for quality control because both genotype and clinical data were available for these samples. Quality control is described below in more detail. 306 of the 976 samples were not considered for quality control because while genotype data was available, clinical data was not available, for example, due to screen failures.
  • Table 3 Five pairs of duplicated samples. Samples in bold were removed.
  • Table 6 Dataset after Quality Control. Each element is "the number of samples after QC / the number of samples before QC”.
  • stage 1 association testing A two-stage strategy was utilized to identify treatment-specific genomic regions of interest in patients with Schizophrenia.
  • stage 1 an association analysis for tier 1, tier 2, and tier 3 genes or variants (e.g., single nucleotide polymorphisms (S Ps)) was performed within the lurasidone arms.
  • S Ps single nucleotide polymorphisms
  • stage 1 The models for lurasidone-arm association testing (i.e., stage 1) are described below.
  • Change Gene or Variant + Dosage + Trial + Gender + Age + Baseline + PC1-4 (Principal Component Analysis 1-4).
  • Response Gene or Variant + Dosage + Trial + Gender + Age + Baseline + PC1-4.
  • baseline refers to PANSS at baseline.
  • Table 7 Genes or variants that were significant after multiplicity adjustment.
  • the numbers shown in Table 7 were based on the analysis of change of PANSS from baseline.
  • the number of genes within the tiers was specific to gene-level association using common variants, based on the variant availability in the data.
  • the number of variants within the tiers was specific to the endpoint PANSS change from baseline; the numbers for the other endpoints were similar.
  • Table 8 Top five results from LOCF analysis of tier 1 genes with regards to the endpoint
  • Table 9 Tope five results from sensitivity analysis of tier 1 genes with regards to the endpoint
  • Table 10 Top five results from LOCF analysis of tier 3 genes with regards to the endpoint
  • Table 11 Top five results from sensitivity analysis of tier 3 genes with regards to the endpoint
  • Table 12 Top five results from LOCF analysis of tier 3 variants with regards to the endpoint PANSS change from baseline.
  • Table 13 Top five results from sensitivity analysis of tier 3 variants with regards to the endpoint PANSS change from baseline.
  • stage 2 Analysis - stage 2 association testing.
  • the genes or variants were tested for a treatment-specific association via a gene-by-treatment or SNP -by treatment model.
  • the model combined the lurasidone and placebo arms.
  • GRIN2C As described above, the genes GRIN2C, TNFRSF IB and MIR4632 were carried forward to stage 2. GRIN2C was tested for an interaction effect in LOCF analysis, but no statistical evidence was observed for any outcomes. See Table 14. TNFRSFIB and MIR4632 were tested for an interaction effect in sensitivity analysis and statistical evidence was observed for the outcome change in PANSS from baseline. See Table 15.
  • Table 14 LOCF analysis of GRIN2C for the outcomes change of PANSS from baseline and response (Def. 1).
  • Table 15 Sensitivity analysis of TNFRSFIB and MIR4632 for the outcomes change of PANSS from baseline and response (Def. 1).
  • SI subgroup identification
  • refinement started with the 8 detected SNPs (see Table 17) and utilized linkage disequilibrium (LD) pruning and feature selection probability. If high linkage disequilibrium occurred between selected SNPs, then LD pruning was used to remove SNPs. LD pruning used a threshold of R 2 greater than 0.8 and removed the SNP rs542282.
  • Feature selection probability identified SNPs having a high probability of being selected based upon bootstraps. Specifically, the data was resampled (e.g., 100 bootstrap samples) and for each bootstrap, the subgroup score was refitted. From the 100 bootstrap samples, SNPs with non-zero coefficient probability greater than 80% or 90% were selected. See FIG. 2 and Table 18. A total of 6 SNPs were considered with a probability threshold of 80% while a total of 3 SNPs were considered with a probability threshold of 90%. These 6 SNPs were rsl0512247, rsl061628, rsl442377, rs522807, rsl7879121, and rs496888.
  • Table 19 Subgroup for combined lurasidone arms and olanzapine.
  • FIGS. 3 and 9 demonstrated that individuals with the 6 SNPs exhibited improved PANSS total score when administered lurasidone.
  • the bootstrap p value was 0.0036.
  • the treatment by subgroup interaction p-value was 0.001.
  • the Least Square (LS) mean in the combined lurasidone arm, when the subgroup was not considered, was -25.23 (-27.36, -23.11).
  • the LS mean in the subgroup for the combined lurasidone arm was -31.37 (-34.61, -28.13).
  • This 6 SNP model identified the change of PANSS by dosage of lurasidone. See FIG. 5.
  • the LS mean in the combined lurasidone arms when the subgroup was and was not considered is shown in Table 20.
  • the treatment by subgroup interaction p value was 0.009.
  • FIG. 13 shows clinical PANSS change from baseline for the combined treatment arms while FIGS. 14, 15, and 16 show the change of clinical PANSS from baseline with the 6- SNP biomarker (BM) positive (BMpos) and negative (BMneg) for 40 mg, 80 mg, and 120 mg lurasidone, respectively.
  • Treatment odds ratio (OR) within the subgroup was 2.83 (1.23, 6.52).
  • Treatment OR outside of the subgroup was 0.64 (0.33, 1.25).
  • Treatment OR overall was 1.18 (0.71, 1.95).
  • Treatment by subgroup interaction p value was 0.006.
  • the mean response rate based on transformed LS means in the combined lurasidone arms was as follows: when not considering the subgroup, 0.44 (0.37, 0.51), and within the subgroup, 0.60 (0.49, 0.70). Accordingly, individuals within the subgroup were 1.37 times more likely to respond to lurasidone treatment.
  • Tables 21 and 23 show the 6 S Ps that significantly correlated with change of PANSS, change of PANSS by dosage, and response rate.
  • Table 22 shows the calculated genotype frequency for each SNP for the categories In Subgroup, Outside Subgroup, and Overall.
  • Table 22 Genotype frequency for each SNP for the categories In Subgroup, Outside Subgroup, and Overall.
  • this 6 variant (6 SNP) model showed statistically significant evidence for a treatment-specific effect.
  • a subgroup identified via the genetic signature set forth in Table 21 showed statistically significant enhanced treatment effect. See FIGS. 3-5, 9, and 10. Moreover, the subjects outside the subgroup showed a statistically significant non-response rate.
  • the dataset was bootstrapped 1000 times, and each bootstrapped dataset was used to re-estimate a score using elastic net. If the biomarker was not selected in one of the bootstrap runs, then the coefficient was zero for that bootstrap run. Using this approach, a coefficient range for each SNP was estimated at a 95% confidence interval (CI) using 2.5% and 97.5%) percentiles of the 1000 estimates. The 95% CI coefficient ranges are set forth in Table 23.
  • G was 0, 1, or 2, depending on the patient's allele combination (see Table 23) and coefficient ⁇ was selected from within the range provided for each particular variant (also see Table 23).
  • Score, - (rs522807 coefficient) * rs522807 G value - (rs496888 coefficient) * rs496888 G value - (rsl7879121 coefficient) * rsl7879121 G value - (rs 1061628 coefficient) * rs 1061628 G value - (rs 10512247 coefficient) * rsl0512247 G value - (rs 1442377 coefficient) * rs 1442377 G value
  • G was 0, 1, or 2, depending on the patient's allele combination (see Table 23) and coefficient ⁇ was selected from within the range provided for each particular variant (also see Table 23).
  • Score (rs522807 coefficient) * rs522807 G value + (rs496888 coefficient) * rs496888 G value + (rsl7879121 coefficient) * rsl7879121 G value + (rsl061628 coefficient) * rs 1061628 G value + (rs 10512247 coefficient) * rsl0512247 G value + (rs 1442377 coefficient) * rs 1442377 G value
  • Example 3 the analysis described herein in Example 3 was with respect to the combination of study 229 and study 231.
  • Table 24 Subgroup for combined lurasidone arms and olanzapine.
  • FIGS. 6 and 11 demonstrated that individuals with the 3 SNPs exhibited improved PANSS total score when administered lurasidone.
  • the bootstrap p value was 0.007.
  • the LS mean in the subgroup was -29.72 (-32.99, -26.46).
  • This 3 SNP model identified change of PANSS by dosage of lurasidone. See FIG. 8.
  • the LS mean in the combined lurasidone arms when the subgroup was and was not considered is shown in Table 25.
  • the treatment by subgroup interaction p value was 0.0003.
  • FIG. 13 shows clinical PANSS change from baseline for the combined treatment arms while FIGS. 17, 18, and 19 show the change of clinical PANSS from baseline with the 3-SNP biomarker (BM) positive (BMpos) and negative (BMneg) for 40 mg, 80 mg, and 120 mg lurasidone, respectively.
  • Table 25 LS mean in the combined lurasidone arms for change of PANSS by dosage of lurasidone.
  • the 3 SNP model also identified the response rate to lurasidone treatment. See FIGS. 7 and 12. Treatment OR within the subgroup was 3.39 (1.39, 8.51). Treatment OR outside of the subgroup was 0.59 (0.30, 1.14). Treatment OR overall was 1.18 (0.71, 1.95). Treatment by subgroup interaction p value was 0.001.
  • the mean response rate based on transformed LS means in the combined lurasidone arms was as follows: when not considering the subgroup, 0.44 (0.37, 0.51), and within the subgroup 0.54 (0.43, 0.64). Accordingly, individuals within the subgroup were 1.22 times more likely to respond to lurasidone treatment.
  • Tables 26 and 28 show the 3 SNPs that significantly correlated with change of PANSS, change of PANSS by dosage, and response rate.
  • Table 27 shows the calculated genotype frequency for each SNP for the categories In Subgroup, Outside Subgroup, and Overall.
  • Table 27 Genotype frequency for each SNP for the categories In Subgroup, Outside Subgroup, and Overall.
  • this 3 variant (3 SNP) model showed statistically significant evidence for a treatment-specific effect.
  • a subgroup identified via the genetic signature set forth in Table 26 showed statistically significant enhanced treatment effect. See FIGS. 6-8, 11, and 12. Moreover, the subjects outside the subgroup showed a statistically significant non-response rate.
  • the dataset was bootstrapped 1000 times, and each bootstrapped dataset was used to re-estimate a score using elastic net. If the biomarker was not selected in one of the bootstrap runs, then the coefficient was zero for that bootstrap run. Using this approach, a coefficient range for each SNP was estimated at a 95% confidence interval (CI) using 2.5% and 97.5%) percentiles of the 1000 estimates. The 95% CI coefficient ranges are set forth in Table 28. [00163] Using these coefficients, for each signature, the patient's score was calculated as follows when the outcome was change of PANS S from baseline:
  • G was 0, 1, or 2, depending on the patient's allele combination (see Table 28) and coefficient ⁇ was selected from within the range provided for each particular variant (also see Table 28).
  • Score, - (rsl061628 coefficient) * rsl061628 G value - (rsl0512247 coefficient) * rs 10512247 G value - (rs 1442377) * rs 1442377 G value
  • G was 0, 1, or 2, depending on the patient's allele combination (see Table 28) and coefficient ⁇ was selected from within the range provided for each particular variant (also see Table 28).
  • Score, (rsl061628 coefficient) * rsl061628 G value + (rsl0512247 coefficient) * rs 10512247 G value + (rs 1442377) * rs 1442377 G value
  • Examples 1, 2, and 3 describe the analysis with respect to the combination of studies 229 and 231.
  • Study 229 and study 231 were also evaluated separately with regards to the 3 SNP and 6 SNP models.
  • Table 29 summarizes the evaluation of treatment by subgroup interaction p-value with respect to the outcomes change of PANS S and response rate for the combination of studies 229 and 231 (i.e., "all"), study 229, and study 231.
  • Table 29 Summary of the evaluation of the 3-SNP and 6-SNP models.
  • a method for treating schizophrenia in an individual comprising administering lurasidone to an individual identified as (i) TNFRSFIB variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSFIB variant positive and DLGAPl variant positive, (v) TNFRSFIB variant positive and intergenic variant positive, (vi) DLGAPl variant positive and intergenic variant positive, or (vii) TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Clause 5 The method of clause 1, wherein the individual is TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive.
  • a method for determining the likelihood that an individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone comprising: obtaining a biological sample from the individual; assaying the sample for the presence or absence of a TNFRSF1B variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual; and determining if the individual is likely to experience an enhanced treatment effect as compared to an individual who has been treated with a placebo when the TNFRSF1B variant and/or the DLGAPl variant and/or the intergenic variant are detected in the sample, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Clause 19 The method of clause 13, comprising detecting the presence of a
  • TNFRSFIB variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual are TNFRSFIB variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual.
  • Clause 20 The method of clause 13, wherein the sample is selected from the group consisting of a body fluid sample, a tissue sample, cells and isolated nucleic acids.
  • Clause 22 The method of clause 20, wherein the isolated nucleic acids comprise RNA.
  • Clause 23 The method of clause 22, wherein the assaying comprises reverse transcribing the RNA to produce cDNA.
  • Clause 24 A method for treating schizophrenia in an individual identified as (i) TNFRSFIB variant positive, (ii) DLGAPl variant positive, (iii) intergenic variant positive, (iv) TNFRSFIB variant positive and DLGAPl variant positive, (v) TNFRSFIB variant positive and intergenic variant positive, (vi) DLGAPl variant positive and intergenic variant positive, or (vii) TNFRSFIB variant positive, DLGAPl variant positive, and intergenic variant positive, the method comprising administering lurasidone to the individual, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Clause 25 The method of clause 24, wherein the TNFRSFIB variant is selected from the group consisting of rsl061628, rs522807, rs496888, rsl7879121, and combinations thereof.
  • Clause 28 The method of clause 24, wherein the individual is TNFRSFIB variant positive, DLGAP1 variant positive, and intergenic variant positive.
  • Clause 34 The method of clause 24, wherein the individual has rsl061628, rsl0512247, and rsl442377 variants.
  • a method for determining the likelihood that a first individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone as compared to a second individual who has been treated with a placebo comprising: obtaining a biological sample from the first individual; assaying the sample to determine the presence or absence of a TNFRSFIB variant and/or a DLGAPl variant and/or intergenic variant in nucleic acids from the first individual; and determining the first individual is likely to experience an enhanced treatment effect when treated with lurasidone if (i) a TNFRSFIB variant positive, (ii) a DLGAP1 variant positive, (iii) a intergenic variant positive, (iv) a TNFRSFIB variant positive and a DLGAP1 variant positive, (v) a TNFRSFIB variant positive and a intergenic variant positive, (vi) a DLGAP1 variant positive and a intergenic variant positive, or (vii) a TNFRSFIB variant
  • a method for determining the likelihood that an individual suffering from schizophrenia will respond favorably to treatment with lurasidone comprising: obtaining a biological sample from the individual; assaying the sample from the individual to determine the presence of a TNFRSF1B variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the individual; and determining the individual is likely to respond favorably to treatment with lurasidone when the individual is (i) TNFRSF1B variant positive, (ii) DLGAP1 variant positive, (iii) intergenic variant positive, (iv) TNFRSF1B variant positive and DLGAP1 variant positive, (v) TNFRSF1B variant positive and intergenic variant positive, (vi) DLGAP1 variant positive and intergenic variant positive, or (vi) TNFRSF1B variant positive, DLGAP1 variant positive, and intergenic variant positive, wherein the intergenic variant is located from position 95,934,021 on chromosome
  • Clause 48 The method of clause 42, wherein the sample is selected from the group consisting of a body fluid sample, a tissue sample, cells and isolated nucleic acids.
  • Clause 50 The method of clause 48, wherein the isolated nucleic acids comprise RNA.
  • Clause 51 The method of clause 50, wherein the assaying comprises reverse transcribing the RNA to produce cDNA.
  • Clause 52 The method of clause 42, wherein the assaying comprises nucleic acid sequencing.
  • a method of determining the likelihood that a first individual suffering from schizophrenia will experience an enhanced treatment effect when treated with lurasidone as compared to a second individual who has been treated with a placebo comprising the steps of: (a) assaying in a sample obtained from the first individual for the presence or absence of a TNFRSF1B variant and/or a DLGAPl variant and/or an intergenic variant in nucleic acids from the first individual; (b) assigning a first value to the presence or absence of the TNFRSF1B variant, a second value to the presence or absence of the DLGAPl variant, and/or a third value to the presence or absence of the intergenic variant in nucleic acids from the first individual; (c) combining the first value, second value, and third value in step b to obtain a total score for the first individual; (d) comparing the total score determined in step c with a predetermined total score; and (e) determining if the first individual is likely to experience an
  • Clause 54 The method of clause 53, wherein the first value is a product of a rsl061628 coefficient and rs 1061628 G value.
  • Clause 55 The method of clause 53, wherein the first value is a combination of (a) a product of a rs 1061628 coefficient and rs 1061628 G value; (b) a product of a rs522807 coefficient and rs522807 G value; (c) a product of a rs496888 coefficient and rs496888 G value; and (d) a product of a rs 17879121 coefficient and rs 17879121 G value.
  • Clause 56 The method of clause 53, wherein the second value is a product of a rsl442377 coefficient and rs 1442377 G value.
  • Clause 58 The method of clause 53, wherein the TNFRSF1B variant is selected from the group consisting of rsl061628, rs522807, rs496888, rsl7879121, and combinations thereof.
  • Clause 63 The method of clause 53, comprising detecting the presence of the TNFRSFIB variant and/or the DLGAPl variant and/or the intergenic variant in nucleic acids from the first individual.
  • Clause 64 The method of clause 53, wherein the sample is selected from the group consisting of a body fluid sample, a tissue sample, cells and isolated nucleic acids.
  • Clause 65 The method of clause 64, wherein the isolated nucleic acids comprise DNA.
  • Clause 66 The method of clause 64, wherein the isolated nucleic acids comprise RNA.
  • Clause 67 The method of clause 66, wherein the assaying comprises reverse transcribing the RNA to produce cDNA.
  • a kit comprising a primer pair for detecting a TNFRSFIB variant and/or a primer pair for detecting a DLGAPl variant and/or a primer pair for detecting an intergenic variant in nucleic acids from an individual, wherein the intergenic variant is located from position 95,934,021 on chromosome 9 to position 95,934,221 on chromosome 9.
  • Clause 70 The kit of clause 69, wherein the TNFRSFIB variant is rsl061628.

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Abstract

La présente invention concerne des procédés de traitement de la schizophrénie chez un individu. L'invention concerne en outre des procédés de détermination du fait qu'un individu souffrant de dépression est ou non susceptible de répondre favorablement ou de bénéficier d'un effet de traitement augmenté en réponse au traitement avec la lurasidone. Les procédés comprennent la détermination de la présence de polymorphismes dans le gène du membre IB de la superfamille du récepteur du facteur de nécrose Tumorale (TNFRSF1B) et/ou le gène de la protéine associée aux grands disques 1 (DLGAP1) et/ou des régions intergéniques dans l'individu.
PCT/US2016/015760 2015-01-30 2016-01-29 Procédé de traitement de la schizophrénie comprenant l'administration de lurasidone WO2016123543A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11481781B2 (en) 2013-12-18 2022-10-25 PayRange Inc. Processing interrupted transaction over non-persistent network connections

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4656127A (en) 1983-04-22 1987-04-07 Amersham International Plc. Method of detecting mutations in DNA and RNA
WO1991002087A1 (fr) 1989-08-11 1991-02-21 Bertin & Cie Procede rapide de detection et/ou d'identification d'une seule base sur une sequence d'acide nucleique, et ses applications
US5639611A (en) 1988-12-12 1997-06-17 City Of Hope Allele specific polymerase chain reaction
US20140274764A1 (en) * 2013-03-15 2014-09-18 Pathway Genomics Corporation Method and system to predict response to treatments for mental disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4656127A (en) 1983-04-22 1987-04-07 Amersham International Plc. Method of detecting mutations in DNA and RNA
US5639611A (en) 1988-12-12 1997-06-17 City Of Hope Allele specific polymerase chain reaction
WO1991002087A1 (fr) 1989-08-11 1991-02-21 Bertin & Cie Procede rapide de detection et/ou d'identification d'une seule base sur une sequence d'acide nucleique, et ses applications
US20140274764A1 (en) * 2013-03-15 2014-09-18 Pathway Genomics Corporation Method and system to predict response to treatments for mental disorders

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
DATABASE SNP [online] 11 November 2003 (2003-11-11), "Submitted SNP(ss) Report in Submission Format: rs1442377", XP002758133, retrieved from NCBI Database accession no. ss2255031 *
DATABASE SNP [online] 13 November 2003 (2003-11-13), "Submitted SNP(ss) Report in Submission Format: rs10512247", XP002758134, retrieved from NCBI Database accession no. ss14910779 *
DATABASE SNP [online] 13 September 2000 (2000-09-13), "Submitted SNP(ss) Report in Submission Format: rs1061628", XP002758129, retrieved from NCBI Database accession no. ss1546754 *
DATABASE SNP [online] 27 July 2000 (2000-07-27), "Submitted SNP(ss) Report in Submission Format: rs496888", XP002758131, retrieved from NCBI Database accession no. ss666774 *
DATABASE SNP [online] 27 July 2000 (2000-07-27), "Submitted SNP(ss) Report in Submission Format: rs522807", XP002758130, retrieved from NCBI Database accession no. ss693175 *
DATABASE SNP [online] 8 November 2004 (2004-11-08), "Submitted SNP(ss) Report in Submission Format: rs17879121", XP002758132, retrieved from NCBI Database accession no. ss28528865 *
ELGHANIAN R ET AL., SCIENCE, vol. 277, 1997, pages 1078 - 1081
GIBBS ET AL., NUCLEIC ACIDS RES., vol. 17, 1989, pages 2437 - 2448
GROMPE M ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 5855 - 5892
GROMPE M, NATURE GENETICS, vol. 5, 1993, pages 111 - 117
KARET, F. E. ET AL., ANALYTICAL BIOCHEMISTRY, vol. 220, 1994, pages 384 - 390
LI ET AL.: "A multi-marker molecular signature approach for treatment-specific subgroup identification with survival outcomes", THE PHARMACOGENOMICS JOURNAL, vol. 14, no. 5, 2014, pages 439 - 45
MANIATIS ET AL.: "Molecular Cloning, A Laboratory Manual", 1989, COLD SPRING HARBOR LABORATORY PRESS, pages: 16.4
NYREN, P. ET AL., ANAL. BIOCHEM., vol. 208, 1993, pages 171 - 175
ORITA M ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 2766 - 2770
SHEFFIELD V C ET AL., AM. J. HUM. GENET, vol. 49, 1991, pages 699 - 706
WANG, A. M. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 9717 - 9721
WHITE M B ET AL., GENOMICS, vol. 12, 1992, pages 301 - 306
WIEDMANN ET AL., PCRMETHODS APPL., vol. 3, 1994, pages 551 - 564

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11481781B2 (en) 2013-12-18 2022-10-25 PayRange Inc. Processing interrupted transaction over non-persistent network connections

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