Method of treatment using genetic predictors of a response to treatment with CRHR1 antagonists
Methods of treating a condition which is treatable with SSR-125543 or a pharmaceutically acceptable salt thereof in a subject in need thereof are provided. The methods of treatment include predicting a treatment response of a subject to a treatment with SSR-125543 and/or detecting a polymorphism genotype associated with a treatment response of a subject to treatment with SSR-125543. Sets of at least one polymorphism genotype useful in the predicting and/or detecting steps are also disclosed.
1 . A method of treating a subject having a condition characterized, caused or accompanied by CRH overproduction or over-activity, comprising
(a) detecting at least one polymorphism genotype selected from the group consisting of rs11715827 [G], rs2044070 [G], rs2028629 [G] and rs6026567 [G] in a biological sample from the subject,
(b) after step (a), diagnosing the subject as a SSR-125543 responder, or having an increased likelihood of responding to SSR-125543, and
(c) administering an effective amount of SSR-125543 or a pharmaceutically acceptable salt thereof to the subject diagnosed as a SSR-125543 responder.
2 . The method of claim 1 , wherein the diagnosing step comprises one or more statistical analysis method selected from the group consisting of artificial neural network learning, decision tree learning, decision tree forest learning, linear discriminant analysis, non-linear discriminant analysis, genetic expression programming, relevance vector machines, linear models, generalized linear models, generalized estimating equations, generalized linear mixed models, the elastic net, the lasso support vector machine learning, Bayesian network learning, probabilistic neural network learning, clustering, and regression analysis, optionally wherein the statistical analysis method is computer-implemented.
3 . The method of claim 1 , wherein the SSR-125543 responder has a clinical response.
4 . The method of claim 1 , wherein the subject has depressive symptoms, anxiety symptoms or both depressive symptoms and anxiety symptoms or a sleep disorder; and/or
wherein the SSR-125543 or a pharmaceutically acceptable salt thereof treats depressive symptoms, anxiety symptoms or both depressive symptoms and anxiety symptoms or a sleep disorder.
5 . The method of claim 3 , wherein the clinical response is a prevention, alteration, alleviation or complete remission of depressive symptoms and/or anxiety symptoms or a sleep disorder.
6 . The method of claim 3 , wherein the clinical response is a prevention, alteration, alleviation or complete remission of depressive symptoms and/or anxiety symptoms as determined using a scale selected from the group consisting of HAM-D, BDI, MADRS, GDS, ZSRDS, HAM-A and STAI.
7 . The method of claim 1 , wherein the biological sample is a buccal or a blood sample.
8 . The method of claim 1 , wherein detecting comprises the use of one or more polynucleotides capable of specifically hybridizing to at least one nucleic acid comprising the one or more polymorphism genotypes.
9 . The method of claim 1 , wherein the subject diagnosed as a SSR-125543 responder has a sensitivity of higher than 50% and a specificity of higher than 50%.
10 . The method of claim 1 , wherein the one or more polymorphism genotypes comprise at least one polymorphism genotype selected from the group consisting of rs11715827 [G], rs2044070 [G], rs2028629 [G], and rs6026567 [G] in combination with at least one polymorphism genotype selected from the group consisting of rs17740874 [T], rs3811939 [G], rs1882478 [G], rs2235013 [T], rs2214102 [T], rs6415328 [C], rs77152456 [A], rs66794218 [A], rs2589476 [T], rs118003903 [G], rs11871392 [T], rs2589487 [C], rs74338736 [C], rs6026593 [G] and rs6520908 [T].
11 . The method of claim 10 , wherein the one or more polymorphism genotypes comprise:
(a) at least two;
(b) at least four;
(c) at least eight;
(d) at least sixteen; or
(e) all of the polymorphism genotypes as defined in claim 10 .
12 . A method of treating comprising,
(a) detecting at least one polymorphism genotype selected from the group consisting of rs11715827 [G], rs2044070 [G], rs2028629 [G] and rs6026567 [G] in a biological sample from a subject, wherein detecting comprises using a kit comprising:
i) at least one polynucleotide capable of specifically hybridizing to a nucleic acid comprising at least one polymorphism genotype selected from the group consisting of rs11715827 [G], rs2044070 [G], rs2028629 [G] and rs6026567 [G], and
ii) one or more additional reagents for detecting the presence of the one or more polymorphism genotypes,
(b) diagnosing the subject as a SSR-125543 responder, or having an increased likelihood of responding to SSR-125543, when one or more of rs11715827 [G], rs2044070 [G], rs2028629 [G] and rs6026567 [G] are present; and
(c) administering SSR-125543 to the subject diagnosed as a SSR-125543 responder.
13 . The method of claim 12 , wherein the kit comprises at least one polynucleotide bound to a solid support.
14 . The method of claim 12 , wherein the kit comprises at least one polynucleotide bound to the solid support in the form of an array.
15 . The method of claim 1 , wherein the detecting step comprises a method selected from the group consisting of allele-specific oligonucleotide (ASO)-dot blot analysis, primer extension assays, iPLEX polymorphism/SNP genotyping, dynamic allele-specific hybridization (DASH) genotyping, the use of molecular beacons, tetra primer ARMS PCR, a flap endonuclease invader assay, an oligonucleotide ligase assay, PCR-single strand conformation polymorphism (SSCP) analysis, quantitative real-time PCR assay, polymorphism/SNP microarray based analysis, restriction enzyme fragment length polymorphism (RFLP) analysis, targeted resequencing analysis and whole genome sequencing analysis.
16 . A method of treating comprising:
(a) detecting at least one polymorphism genotype selected from the group consisting of rs11715827 [G], rs2044070 [G], rs2028629 [G] and rs6026567 [G] in a biological sample from a subject;
(b) diagnosing the subject as a SSR-125543 responder, or having an increased likelihood of responding to SSR-125543; and
(c) administering SSR-125543 or a pharmaceutically acceptable salt thereof to the subject diagnosed as a SSR-125543 responder.