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(12) Patent Application Publication (10) Pub. No.: US 2006/0253262 A1 Ching Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0253262 A1 Ching Et Al US 20060253262A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0253262 A1 Ching et al. (43) Pub. Date: Nov. 9, 2006 (54) NOVELMETHODS AND DEVICES FOR Related U.S. Application Data EVALUATING POISONS (60) Provisional application No. 60/778,133, filed on Mar. (75) Inventors: Edwin P. Ching, Woodside, CA (US); 1, 2006. Provisional application No. 60/675,741, filed Dale E. Johnson, Emeryville, CA (US); on Apr. 27, 2005. Sucha Sudarsanam, Greenbrae, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. WILSON SONSN GOODRCH & ROSAT G06F 9/00 (2006.01) 650 PAGE MILL ROAD (52) U.S. Cl. ................................................................ 702/20 PALO ALTO, CA 94304-1050 (US) (73) Assignee: Emiliem, Emeryville, CA (US) (57) ABSTRACT (21) Appl. No.: 11/380,388 Methods and devices useful for evaluating poisons or other chemical entities, and for using Such methods to forecast (22) Filed: Apr. 26, 2006 unfavorable drug effects. US 2006/0253262 A1 Nov. 9, 2006 NOVEL METHODS AND DEVICES FOR defined biological context. This is both a costly and labori EVALUATING POISONS ous process, which requires enormous investment in finan cial and other resources. This fact is recognized by the US PRIORITY CLAIM FDA and other national drug regulatory agencies. It has been 0001. This application claims priority to U.S. Provisional stated that commercially available tests for safety monitor Application Ser. No. 60/778,133, filed Mar. 1, 2006 and U.S. ing (biomarkers) are urgently needed, and Such remains the Provisional Application Ser. No. 60/675,741, filed Apr. 27, least developed area of pharmacogenomic monitoring and 2005. All the above cited United States provisional appli individualized medical treatment. cations are expressly incorporated herein by reference in 0006 Citation of documents above and hereafter is not their entirety. intended as an admission that any is pertinent prior art. All statements as to the date or representation as to the contents FIELD OF THE INVENTION of documents is based on the information available to the 0002 The invention relates to methods and devices for applicant and does not constitute any admission as to the evaluating poisons and other therapeutic entities. Some of correctness of the dates or contents of the documents. the methods and uses are related directly to unfavorable drug effects, and others will be more widely applicable to generic SUMMARY OF THE INVENTION evaluation of pharmacology and therapeutic index. 0007. The present invention is directed to accelerating the speed of development and reducing the resource investment BACKGROUND OF THE INVENTION necessary to determine these features for directing use of 0003. Developing a new therapeutic drug candidate from Such substances or treatments to appropriate biological initial concept to market sales typically requires from 12 to COInteXtS. 15 years of research and development time, and has been 0008. The present invention provides lists of biomarkers estimated to require investing nearly one billion dollars. See, for analysis, either directly or indirectly, which affect the e.g., UBS Warburg Report, Charles River Laboratories, Feb. toxicity pathways. These may be evaluated at many levels, 28, 2003, pages 7-8; and www.fda.gov. A significant portion including genetic, genotyping, evaluation of combination of these expenditures occurs during preclinical animal test pairing of diploid alleles or haplotypes, RNA expression, ing, and even more is spent on human clinical safety and protein expression, functional activity, post-translational efficacy testing. Pharmacology or toxicology problems analysis or evaluation, etc. Thus, the biomarkers refer to the which remain undetected until later stages of drug develop corresponding genetic information, RNA, protein, or other ment are extremely problematic, both in terms of dollar structural embodiments thereof. And the means to use these expenditures and lost time. And the situation is even worse biomarkers, e.g., to evaluate status of toxicity pathways, to if toxicity problems remain undetected until after market evaluate individual risk or susceptibility to various toxic introduction. Thus, early and accurate assessment of safety pathways from exposure or therapeutic intervention, to and efficacy of candidate therapeutic entities, along with generate test systems for drug development, are all provided proper administration and treatment methods, is indispens by identifying critical and significant contributors to the able to efficient development of new therapeutic entities. pathway progression. Pharmacology is a science directed to the study of the action of Substances, typically chemicals and other entities, on 0009. The invention further provides methods for detect biological systems. This encompasses both pharmacody ing the state of a toxicity pathway in a primate, said method namics and pharmacokinetics. See, e.g., Berkow, et al. The comprising evaluating the form or function of a discrimi Merck Manual Merck and Co.; Hardman, et al (eds. 2001) natory biomarker selected from: (a) Table 4. Subset 1; (b) Goodman and Gilman's. The Pharmacological Basis of Table 4, subset 2; (c) Table 4, subset 3; (d) Table 3A or 6A, Therapeutics (10th Ed.) McGraw-Hill, ISBN: 0071354697: subsets 2 or 3: Table 3A or 6A, subset 1: Table 2A or 5A, and other academic and professional School textbooks used subsets 2 or 3; and (e) Table 2A or 5A, subset 1. Specific in teaching pharmacology. The US Food and Drug Admin datasets also provide various markers, individually or in istration (FDA) is concerned with virtually all aspects of use various combinations. Various pluralities or combinations of of substances in therapeutic or diagnostic contexts. See, e.g., those markers are important in liver or other toxicity path www.fda.gov. ways. In various embodiments: the toxicity pathway is affected in response to a therapeutic treatment, including 0004. A closely related area of relevance is toxicology, administration of a drug or combination of therapies; the which addresses features and properties of Substances which primate is a chimpanzee; the form of evaluating is determi may have specific defined effects on the systems, typically nation of genetic presence of a specific allelic form or leading to negative or undesirable effects. See, e.g., Klaas specific combination of diploid alleles of said discriminatory sen, et al. (eds. 2001) Casarett and Doull's Toxicology. The biomarker; the form of evaluating is expression at a nucleic Basic Science of Poisons (6th ed.) McGraw-Hill, ISBN: acid or protein level, including allelic diploid combinations 0071347216; and Hayes (ed. 2001) Principles and Methods of said discriminatory biomarker; the form of evaluating is of Toxicology (4th Ed.) CRC Press, ISBN: 1560328142; and a protein evaluation, including an immunoassay, modifica other academic and professional School textbooks used in tion, quantitation, mass spectroscopy, NMR, imaging, or teaching toxicology. characteristic temporal pattern determination; the form of 0005. However, elucidating the pharmacology and toxi evaluation is determination of functional activity of said cology of a Substance, e.g., a therapeutic entity or potential discriminatory biomarker, including a detectable Substrate new treatment, requires a significant amount of study to or product of an enzymatic activity affected by said biom determine the optimal means and methods for use in a arker; the form of evaluation is expression or functional US 2006/0253262 A1 Nov. 9, 2006 localization of said discriminatory biomarker in said pri derived from a vertebrate; are evaluated by characterization mate, including imaging or localization; the evaluating is of protein features, e.g., by ELISA; or include some haplo from a blood, hair, skin, saliva, or accessible body fluid types from a primate; or the biological system is: a soluble sample or part; the evaluation includes a plurality of dis test system; a cell line; an organ system; or an animal; or the criminatory biomarkers in said Subsets, including biomark correlating is: performed on a computer, which collates data ers from a plurality of different subsets, including from to generate a file of particular identified combinations of Tables 2A/B, 3A/B, 4, 5A/B, or 6A/B; or the evaluation is alleles which exhibit defined categories of risk from said a non-invasive method, including an imaging agent or status of said toxicity pathway; or used to develop a set of detectable or labeled compound. combination diploid haplotypes which are correlated and validated to be incorporated into a diagnostic product, 0010 Based upon these identified biomarkers, the inven including one useful to predict toxicity pathway status in a tion provides label, diagnostic reagent, or diagnostic means Subject. directed to the identified discriminatory biomarker(s); and various kits comprising such and instructions or devices for 0015 The invention further provides methods of identi using Such and/or interpreting the results there from. fying additional relevant genes as candidate test targets for toxicity pathway evaluation, by taking a first list of candi 0011. In preferred embodiments, the kit: (i) evaluates a date targets and identifying a second list of additional multiplicity of biomarkers from Table 4; (ii) is designed to candidate targets: (1) which in an interaction database have evaluate or distinguish between a plurality of defined liver been reported to interact physically with said
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