WO2010111080A2 - Traitement optimisé de la schizophrénie - Google Patents

Traitement optimisé de la schizophrénie Download PDF

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WO2010111080A2
WO2010111080A2 PCT/US2010/027577 US2010027577W WO2010111080A2 WO 2010111080 A2 WO2010111080 A2 WO 2010111080A2 US 2010027577 W US2010027577 W US 2010027577W WO 2010111080 A2 WO2010111080 A2 WO 2010111080A2
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single nucleotide
nucleotide polymorphisms
tables
htr2a
group
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PCT/US2010/027577
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WO2010111080A3 (fr
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Anncatherine Marie Downing
Bruce Jerome Kinon
Sandra Louise Close Kirkwood
Wenlei Liu
Laura Kay Nisenbaum
Reuben Kirobi Njau
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Eli Lilly And Company
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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
    • 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

Definitions

  • the present invention relates to methods of treating schizophrenia with Group II metabotropic glutamate (mGlu) receptor agonists wherein genetic variants are used to predict the clinical outcome of therapy. More particularly, the present invention relates to a method of treating a patient suffering from schizophrenia with LY2140023 monohydrate wherein the patient has one or more variants in one or more of genes HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • mGlu metabotropic glutamate
  • the mGlu receptors are G-protein-coupled receptors that modulate neuronal excitability. More particularly, altered glutamate neurotransmission has been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors.
  • Various studies support Group II mGlu receptor activation for the treatment for schizophrenia (Conn et al, Trends in Pharm. ScL (2009) 30(1), 25-31; Chavez-Noriega et al, Current Drug Targets: CNS & Neurological Disorders (2002) 1(3), 261-281; Schoepp et al , Current Drug Targets: CNS & Neurological Disorders (2002) 1 (2), 215- 225).
  • a mGlu 2/3 receptor agonist has antipsychotic properties and may provide a new alternative for the treatment of schizophrenia (Patil et al, Nature Medicine (2007) 13(3), 1102-1107).
  • mGlu receptor agonists containing a bicyclohexane or heterobicyclohexane ring system
  • WO 96/05175, WO 97/18199, WO 98/51655, WO 00/12464, WO 02/055481, WO 03/104217 One such agonist is LY2140023 monohydrate.
  • This compound has the chemical name (li?,45 r ,5 «S,6 «S')-4-(2'5 r -4'-methylthio-2'-aminobutanonyl)amino-2,2-dioxo- 2 ⁇ 6 -thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid monohydrate and is disclosed in WO 03/104217.
  • a genetic variant is defined as a difference in DNA at a particular locus within a population.
  • genetic variants including mutation, polymorphism, single nucleotide polymorphism (SNP), copy number variant (CNV), copy number polymorphism (CNP), insertion, deletion, duplication, tandem repeat, microsatellite, short tandem repeat (STR), and variable number tandem repeat (VNTR).
  • SNP single nucleotide polymorphism
  • CNV copy number variant
  • CNP copy number polymorphism
  • STR short tandem repeat
  • VNTR variable number tandem repeat
  • SNPs can be linked with patient response to a drug and, thus, used as predictors of a drug's impact on a patient in view of the patient's genetic variation.
  • the present invention provides genetic variants that are useful to predict patient response to treatment for schizophrenia with the Group II (mGlu 2/3) receptor agonist compound LY2140023 monohydrate.
  • the present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention further involves a method of treating schizophrenia in a patient comprising administering an effective amount of LY2140023 monohydrate to a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention also involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention additionally involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or
  • the present invention additionally involves a method of treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention also involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention additionally involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more one or more variants in one or more genes selected from the group consisting of HTR2 A, NRG 1 , DRD2, DRD3 , COMT, GRM3 , and PKHD 1.
  • the present invention also involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3 C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1
  • the present invention further involves the use of LY2140023 monohydrate for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of LY2140023 monohydrate to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3 B, 3 C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention also involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention additionally involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient wherein the patient has one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample; and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention also involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more single nucleotide polymorphisms in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • the present invention involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C and/or one or more single nucleotide polymorphisms in linkage disequilibrium to single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bi
  • the present invention further involves the use of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system for the manufacture of a medicament for treating schizophrenia in a patient comprising obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHD 1 is contained in the DNA sample, and administering an effective amount of a Group II mGlu receptor agonist containing a bicyclohexane or heterobicyclohexane ring system to the patient if the DNA sample contains one or more single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3
  • the present invention also involves a kit for assessing a sample acquired from a patient suffering from schizophrenia comprising DNA extraction reagents; a matrix to which the extracted DNA is bound; contaminant removal reagents; DNA elution solution; oligonucleotide primers and/or probes specific to one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl; genotyping platform reagents; instructions on a genotyping platform for determining whether one or more SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3 A, 3B, 3C in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl is contained in the matrix
  • the present invention provides previously unknown association between genetic variants and the treatment of schizophrenia with a Group II mGlu receptor agonist compound.
  • the detection of these variants provides robust and precise methods for identifying patients that can benefit from using a Group II mGlu receptor agonist in the treatment of schizophrenia.
  • the variant is a single nucleotide polymorphism (SNP).
  • a preferred Group II mGlu receptor agonist is mGlu2/3 receptor agonist LY2140023 monohydrate.
  • genes associated with the treatment of schizophrenia with a Group II mGlu receptor agonist preferably include HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • GeneID information for each gene is as follows: HTR2A (GenelD 3356), NRGl (GenelD 3084), DRD2 (GenelD 1813), DRD3 (GenelD 1814), COMT (GenelD 1312), GRM3 (GenelD 2913 ), and PKHD 1 (GenelD 5314)
  • these genes include HTR2A, NRGl, DRD2, DRD3, and PKHDl. Most preferably, these genes include HTR2A and NRGl. Even more preferably, the genes individually are HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, or PKHDl. More particularly, the SNPs linked to these genes are correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist. These SNPs include the SNPs provided in the Tables (e.g. Tables IA, 2A, 3A) provided herein.
  • SNPs in linkage disequilibrium with these listed SNPs will likewise be correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist.
  • linkage disequilibrium is the tendency for alleles at two linked loci to be associated in the population
  • any SNP in linkage disequilibrium with one or more SNPs that are correlated to the treatment of schizophrenia with a Group II mGlu receptor agonist would, by implication, be itself correlated to the same treatment response.
  • the present invention includes the identification of variants relating to HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl to aid in the prediction of patient outcome and the informed selection of therapies for the use in the treatment of schizophrenia.
  • the present invention employs genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl as the preferred marker.
  • genetic variants in the genes known to be in the biological pathways related to HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl are also markers of success with therapy with an Group II mGlu receptor agonist.
  • the present invention includes use of Group II mGlu receptor agonists for treating schizophrenia in a patient having one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • compounds that are Group II mGlu receptor agonists used for treating schizophrenia in a patent having one or more of these variants contain a pharmacophore associating this agonism to particular atoms within the compounds.
  • compounds within the scope of the present invention have the common structural feature of a bicyclohexane or heterobicyclohexane ring system which is associated with Group II mGlu receptor agonism.
  • the Group II mGlu receptor agonists for treating schizophrenia in a patient having one or more variants in one or more genes selected from the group consisting of HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl are mGlu2/3 receptor agonists.
  • compounds that are mGlu2/3 receptor agonists contain a pharmacophore associating this agonism to particular atoms within the compounds.
  • compounds within the scope of the present invention have the common structural feature of a bicyclohexane or heterobicyclohexane ring system which is associated with mGlu2/3 receptor agonism.
  • the most preferred mGlu2/3 receptor agonist with a heterobicyclohexane ring system is LY2140023 monohydrate.
  • One embodiment of the invention involves a method for determining a patient's response to treatment for schizophrenia with LY2140023 monohydrate by detecting one or more variants in a plurality of genes comprising one or more of the following genes: HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl.
  • PANSS Positive and Negative Syndrome Scale
  • the response is deemed beneficial if there is a significant improvement in the PANSS Total rating scale from baseline after treatment with a Group II mGlu receptor agonist, preferably a mGlu2/3 receptor agonist compound.
  • a patient with one or more genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl will show the greatest response in PANSS Total from baseline and, thus, likely respond to treatment with a Group II mGlu receptor agonist compound, preferably a mGlu2/3 receptor agonist compound, such as LY2140023 monohydrate. More particularly, the response is deemed beneficial if there is a significant improvement in the PANSS Total rating scale from baseline in a patient with schizophrenia after treatment with LY2140023 monohydrate.
  • allele is either of a pair (or series) of alternative forms of a gene that can occupy the same locus on a particular chromosome and that control the same character.
  • chromosome is a structure within the cell that bears the genetic material as a threadlike linear strand of DNA bonded to various proteins in the nucleus.
  • the term "position” is the location of the SNP along the chromosome.
  • DNA sample refers to a sample containing human DNA obtained from, for example, blood, hair, or skin of a patient.
  • the term "effective amount” refers to the amount or dose of a mGlu2/3 agonist compound or pharmaceutically acceptable salt, upon which single or multiple dose administration to a patient, provides the desired treatment.
  • the term “gene” is one or more sequence(s) of nucleotides in a genome that together encode one or more expressed molecule, e.g. an RNA, or polypeptide.
  • genetic variant is a locus that is variable; that is, within a population, the nucleotide sequence at a genetic variant has more than one version.
  • genetic variants including mutation, polymorphism, single nucleotide polymorphism (SNP), copy number variant (CNV), copy number polymorphism (CNP), insertion, deletion, duplication, tandem repeat, microsatellite, short tandem repeat (STR), and variable number tandem repeat (VNTR).
  • SNPs single nucleotide polymorphisms
  • SNPs single base pair difference in the genomic DNA sequence, i.e. the nucleotide at the specified position varies between individuals or populations.
  • genomic refers to all of the genetic information, the entire genetic complement, all of the hereditary material possessed by an organism.
  • major allele refers to the allele that is found in the majority of individuals within a given population.
  • minor allele refers to the allele that is found in the minority of individuals within a given population.
  • major homozygous refers to individuals with two major alleles at a specific locus.
  • heterozygous refers to individuals with one major allele and one minor at a specific locus.
  • minor homozygous refers to individuals with two minor alleles at a specific locus.
  • linkage disequilibrium is the non-random association of alleles at two or more loci.
  • single nucleotide polymorphism is a genetic variant at a single position in a genome, i.e. the nucleotide at the specified position varies between individuals or populations.
  • single nucleotide polymorphisms in linkage disequilibrium with single nucleotide polymorphisms listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C are SNPs in linkage disequilibrium with the SNPs listed in Tables IA, IB, 1C; 2A, 2B, 2C; and/or 3A, 3B, 3C that are associated with the treatment of schizophrenia with a Group II mGlu receptor agonist.
  • This term can also be modified to include different combinations of the noted Tables provided herein.
  • any SNP in linkage disequilibrium with one or more SNPs that are correlated with the treatment of schizophrenia with a Group II mGlu receptor agonist would be itself correlated to the same treatment response.
  • locus is a chromosomal position or region.
  • loci The plural of the term “locus” is "loci.”
  • marker refers to a nucleotide sequence or encoded product thereof (e.g. a protein) used as a point of reference that is predictive of patient outcome when the patient is treated for schizophrenia.
  • patient is a mammal, preferably a human. More preferably, the patient is a Caucasian human.
  • phenotype is a trait or collection of traits that are qualitatively or quantitatively observable in an individual or population.
  • p-value is the probability of obtaining a result at least as extreme as the one that was actually observed, assuming that the null hypothesis is true.
  • treating means slowing, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease.
  • a randomized, three-armed, double-blind, placebo-controlled phase II clinical trial evaluates LY2140023 monohydrate in schizophrenic patients. See Patil et al. (2007) Nature Medicine 13(9): 1102-1107. Pharmacogenomic efforts on DNA samples are collected from this study and are supplemented with DNA samples from a randomized, double-blind, phase IV clinical trial of olanzapine (see Kinon et al., (2008) J CHn Psychopharmacol 28(4): 392-400; HGLF) have been ongoing to identify genetic markers that are associated with improved outcomes for patients treated with LY2140023 monohydrate.
  • SNPs in these genes are detected using standard genotyping technology such as the Sequenom MassARRAY platform.
  • the methodology employs an initial locus-specific PCR reaction, followed by single base extension using mass-modified dideoxynucleotide terminators of an oligonucleotide primer which anneals immediately upstream of the polymorphic site of interest.
  • MALDI-TOF mass spectrometry the distinct mass of the extended primer identifies the SNP allele (Gabriel et al., 2009).
  • ANCOVA ANCOVA
  • the dependent variable is change in PANSS total and the independent variables are gender, baseline PANSS total, age at enrollment, trial (HBBD versus HGLF), treatment, genotype (assuming an additive disease inheritance model) and treatment by genotype interaction Associations between LY2140023 monohydrate response (change in PANSS Total score) and genotypes are identified for SNPs within the HTR2A, NRGl, DRD2, DRD3, COMT, GRM3 and PKHDl genes.
  • PKHDl are associated with improved outcome for subgroups of patients treated with LY2140023 monohydrate. Therefore, a patient with one or more genetic variants in HTR2A, NRGl, DRD2, DRD3, COMT, GRM3, and PKHDl will show the greatest response in PANSS Total and, thus, likely respond to treatment with LY2140023 monohydrate.
  • Tables IA, IB, and 1C involve data for unadjusted p-value ⁇ 0.001.
  • Tables IA, 2A, and 3 A lists the SNPs that are associated with LY2140023 monohydrate treatment response with an unadjusted p value ⁇ 0.001, ⁇ 0.01, and ⁇ 0.05, respectively, along with their related Chromosome, Gene, and Chromosomal Position.
  • the overall p value is listed for the LY2140023 monohydrate group at 28 days of treatment as well as the model based mean change in PANSS Total score for each of the three genotype groups (Major Homozygous, Heterozygous, and Minor Homozygous; see Tables IB, 2B, and 3B).
  • the Minor Allele column lists the nucleotide found in the minority of Caucasian patients within HBBD whereas the Major Allele column lists the nucleotide found in the majority of Caucasian patients within HBBD (see Tables 1C, 2C, and 3C).
  • G is listed as the Minor Allele and A is the Major Allele
  • the Minor Homozygous genotype group will consist of patients with G/G at this SNP, the
  • the Responsive Allele column lists the allele associated with enhanced treatment response (see Tables 1C, 2C, and 3C).
  • the Responsive Genotype Group (e.g. Minor) column lists the genotype group associated with the greatest improvement in PANSS Total score for a particular SNP and the Responsive Genotype identifies the actual genotype associated with the greatest improvement (see Tables 1C, 2C, and 3C).
  • patients with the Responsive Genotype at one of the SNPs would be likely to respond to LY2140023 monohydrate for the treatment of schizophrenia.
  • a double-blind, placebo- and active comparator-controlled trial are conducted in which schizophrenia patients are randomized, to receive 5 mg, 20 mg, 40 mg, or 80 mg twice daily LY2140023 monohydrate, placebo twice daily, or placebo once each morning and 15 mg olanzapine once each evening in a 2:2:2:2: 1 ratio.
  • the methodology employs an initial locus-specific PCR reaction, followed by single base extension using mass-modified dideoxynucleotide terminators of an oligonucleotide primer which anneals immediately upstream of the polymorphic site of interest.
  • mass-modified dideoxynucleotide terminators of an oligonucleotide primer which anneals immediately upstream of the polymorphic site of interest.
  • MALDI-TOF mass spectrometry the distinct mass of the extended primer identifies the SNP allele (Gabriel et al, 2009).
  • the primary response measure has failed to demonstrate statistically significant separation between the treatment group receiving the active comparator (olanzapine) and the placebo-treated group within the intent to treat population in HBBI. Also, the primary response measure (PANSS Total Score) has failed to demonstrate statistically significant separation between the treatment group receiving LY2140023 monohydrate and the placebo-treated group within the intent to treat population in HBBI.
  • the minor homozygous group of the HTR2A SNPs, rs7330461 and rs7330636, and the NRGl SNP, rs 10954863 show the greatest improvement in the PANSS Total Score, similar to what is observed in HBBD for these SNPs.
  • the difference among genotype groups for these SNPs does not reach statistical significance in HBBI.
  • associations are assessed in a second pharmacogenomic analysis in a pre-specified manner, with the strength of evidence encompassing, for example, p-values alone, p-values in combination with multiple testing corrections, or consistencies in the directionality and magnitude of the observed genetic effects on treatment response with those in the first pharmacogenomic analysis.
  • the strength of evidence encompassing, for example, p-values alone, p-values in combination with multiple testing corrections, or consistencies in the directionality and magnitude of the observed genetic effects on treatment response with those in the first pharmacogenomic analysis.
  • a number of options for the genetic subgroup which vary in terms of the SNP(s) involved and how genotypes are grouped, are ranked according to their potential clinical utility, e.g. positive predictive value and/or negative predictive value, which is influenced by the expected proportion and effect size of each subgroup.
  • sample types include, but are not limited to, anti-coagulated whole blood (e.g. citrate, EDTA, or heparin tubes), lymphocytes, saliva, buccal swabs, dried blood spots, plasma, serum, or other body fluids.
  • DNA is extracted from the sample using standard methods and standard DNA extraction reagents. For example, cell lysis typically uses a chaotropic salt such as Guanidine Thiocyanate, binding the extracted DNA to a matrix (e.g. magnetic particles, DNA binding resin). Once the extracted DNA is bound to the matrix, contaminant removal reagents (e.g. alcohol, acetone) are used.
  • a matrix e.g. magnetic particles, DNA binding resin
  • the now purified extracted DNA is eluted from the matrix using the appropriate DNA elution solution (e.g. Tris-based buffer, H 2 O).
  • the appropriate DNA elution solution e.g. Tris-based buffer, H 2 O. See e.g. Riemann et al, J. Clin. Lab. Anal. (2007) 21, 244-248; Baumgartner et ah, Biochemica Newsletter (2005) No. 2.
  • SNP(s) genotype is then used with the chosen genotyping platform to determine the defined SNP(s) genotype.
  • the SNP(s) genotype may be determined using a number of methods. These may include, for example, PCR amplification or direct SNP detection which may be used in a single or multiplex assay (e.g. microarray platforms).
  • the DNA is mixed with the appropriate oligonucleotide primers and/or probes, which are short sequences of DNA surrounding the SNP to be genotyped, and appropriate genotyping platform reagents (e.g. nucleotides, buffers, and Taq Polymerase).
  • genotyping platform reagents e.g. nucleotides, buffers, and Taq Polymerase.
  • This mixture is then cycled through various temperatures that are used to denature the DNA, anneal the primers/probes to the DNA, and finally to extend the DNA using the activity of the Taq Polymerase.
  • fluorescent dyes are incorporated during the extension phase of PCR allowing detection of amplified products. See e.g. Kok et al., Human Mutation (2002) 19, 554-559).
  • the sample DNA is directly hybridized to capture oligonucleotide probes without DNA amplification.
  • these oligonucleotide probes are allele specific and are arrayed onto a solid support (e.g. glass slide, film chip, bead). Additional probes are used to surround the bound DNA and incorporate a fluorescent dye, other light emitting molecule, or electrochemical molecule that is used to visualize or detect the reaction.
  • a solid support e.g. glass slide, film chip, bead.
  • Additional probes are used to surround the bound DNA and incorporate a fluorescent dye, other light emitting molecule, or electrochemical molecule that is used to visualize or detect the reaction.
  • DNA amplified as described above it is also possible for DNA amplified as described above, to be hybridized to a solid support and then detected using oligonucleotide probes to incorporate molecules necessary for detection and/or quantitation. See e.g. Storhoff, et al, Nature Biotechnology (2004) 22 (7), 883-887; Liu et al, IVDT ( May 2008), 31.
  • the reagents and steps described above are done manually or are self-contained in a cartridge utilizing automation and/or microfluidics.
  • a DNA sample is typically supplied with the platform as a positive control sample. This DNA will have a genotype previously confirmed by sequencing or some other validated method, and it is typically included in each run to confirm the assay is reproducible. A negative control sample such as water is typically also included, and it is confirmed that no result is detected.
  • a separate control sample is not typically used but rather internal assay control samples are usually utilized. For example, an array will contain spots designated as image control samples, negative control samples, and possibly assay control samples.
  • the image control samples are designed to react and confirm that the image is being captured. If there is no detection at these spots then it is known there has been a reagent failure. Negative control sample spots serve the same purpose as the negative control sample described above; no DNA is present so no reaction should be detected at these locations. Assay control samples may also be used. These confirm that the probes for the different SNPs are working because they have a known sequence at that location.
  • a kit for assessing a sample acquired from a patient suffering from schizophrenia contains - in addition to the various reagents, matrix, and oligonucleotide primers and/or probes provided herein - instructions on the genotyping platform used and instructions on sample, control sample, and reagent preparation requirements.

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Abstract

La présente invention concerne des procédés de traitement de la schizophrénie avec des agonistes de récepteurs mGlu du Groupe II, des variants génétiques étant utilisés pour prédire l'issue clinique de la thérapie.
PCT/US2010/027577 2009-03-27 2010-03-17 Traitement optimisé de la schizophrénie WO2010111080A2 (fr)

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WO2013177510A1 (fr) * 2012-05-24 2013-11-28 Abbvie Inc. Agonistes des récepteurs nicotiniques neuronaux pour traiter la schizophrénie chez des patients présentant des variantes du gène comt
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012109565A1 (fr) * 2011-02-10 2012-08-16 Neurotherics, Llc Identification génétique de réponse à des médicaments antidépresseurs
WO2013177510A1 (fr) * 2012-05-24 2013-11-28 Abbvie Inc. Agonistes des récepteurs nicotiniques neuronaux pour traiter la schizophrénie chez des patients présentant des variantes du gène comt
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2021046273A1 (fr) * 2019-09-03 2021-03-11 Siekmeier Peter J Méthode d'augmentation de la fonction cognitive au moyen d'un agoniste du récepteur du glutamate
EP4025118A4 (fr) * 2019-09-03 2023-08-09 Peter J. Siekmeier Appareils et procédés d'identification et de traitement de patients sensibles à une thérapie par un agent antipsychotique
EP4025290A4 (fr) * 2019-09-03 2023-08-09 Peter J. Siekmeier Méthode d'augmentation de la fonction cognitive au moyen d'un agoniste du récepteur du glutamate

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