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(12) Patent Application Publication (10) Pub. No.: US 2006/027581.6 A1 Henderson Et Al US 2006027581.6A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/027581.6 A1 Henderson et al. (43) Pub. Date: Dec. 7, 2006 (54) METHODS FOR IDENTIFYING DRUG mechanisms underpinning the pharmacology and toxicology PHARMACOLOGY AND TOXCOLOGY of drug candidates. The methods of the invention identified unique properties relating to apoptosis and the anti-inflam (75) Inventors: Barry Steven Henderson, matory response elicited by several peroxisome proliferator Hillsborough, NC (US); Richard activated receptor gamma (PPARY) ligands. The methods Bentley Cheatham, Durham, NC (US) illustrate, for example, that PPARY ligands that are safe and Correspondence Address: effective drugs (e.g., Actos, Avandia) either do not induce SULLIVAN & WORCESTER LLP apoptosis or only modestly induce apoptosis. Conversely, ONE POST OFFICE SQUARE PPARY ligands that have failed clinical development (e.g., BOSTON, MA 02109 (US) Ciglitazone; Day, C., Diabet. Med., 16: 179-192 (1999)) or that have been withdrawn from the market (e.g., Troglita (73) Assignee: Ribonomics, Inc., Durham, NC Zone (ReZulin)) due to hepatotoxicity are potent inducers of apoptosis. The methods of the invention also illustrate that (21) Appl. No.: 11/446,864 Suppression of gene expression and protein expression for (22) Filed: Jun. 5, 2006 several pro-inflammatory factors by some PPARY ligands occurs as a consequence of apoptotic induction (i.e., apop Related U.S. Application Data tosis produces an anti-inflammatory response). The inven tion also provides biomarkers for cellular pathways and (60) Provisional application No. 60/687.966, filed on Jun. methods for stratifying patient groups according to their 7, 2005. biomarker expression as well as biomarkers that discrimi Publication Classification nate safe and effective drugs from compounds that have acute toxicities. These biomarkers provide novel insights (51) Int. Cl. into the mechanism of action and toxicity for test com CI2O I/68 (2006.01) pounds, including cell death, anti-inflammatory activity, (52) U.S. Cl. .................................................................. 435/6 hepatotoxicity, and carcinogenicity. The methods are highly scalable and have broad application from discovery to the (57) ABSTRACT clinic, including compound prioritization, predictive phar The invention combines a microarray and cell-based screen macology and toxicology: mechanism of action studies; and ing strategy that enables rapid identification of possible prognostic and diagnostic biomarker discovery. Patent Application Publication Dec. 7, 2006 Sheet 1 of 6 US 2006/027581.6 A1 passauddns—* uOISS3/dxE O O Patent Application Publication Dec. 7, 2006 Sheet 2 of 6 US 2006/027581.6 A1 &@@% SpunoduJOO ?u?T||30 Patent Application Publication Dec. 7, 2006 Sheet 3 of 6 US 2006/027581.6 A1 Plate Determine 1)"E Feed & Dose LDso f f ?h Day 1 Day 2 Day 5 Plate Feed & DOSe 150 É 33. %3 % "islator CCssisterone Compound Alone D Compound + Caspase 3/7 inhibitor FIG. 4 Patent Application Publication Dec. 7, 2006 Sheet 4 of 6 US 2006/027581.6 A1 ty 2 Luz -5.0 Pioglitazone Rosiglitazone MCC-555 Troglitazone Ciglitazone FIG. 5A 2400 Pioglitazone Rosiglitazone MCC-555 Troglitazone Ciglitazone FIG. 5B Patent Application Publication Dec. 7, 2006 Sheet 5 of 6 US 2006/027581.6 A1 Treatment 2 Treament + DEVD N N CD – – Piog||— e Rosiglitazone§ MC C-555 Tro taZOne N itazone Cigl FIG. 6A Treatment 2 Treament + DEVO 2100 Ntoco–†c}iç | N|- H D N---- |:|| ||||||| | N | Pioglitazone Rosiglitazone MCC-555 Troglitazone Ciglitazone FIG. 6C Patent Application Publication Dec. 7, 2006 Sheet 6 of 6 US 2006/027581.6 A1 Treatment 2 Treament + DVED Z ZZ 1 Pioglitazone Rosiglitazone MCC-555 Troglitazone Ciglitazone FIG. 6B DTreatment 2 Treament + DEVD Pioglitazone Rosiglitazone MCC-555 Troglitazone Ciglitazone FIG. 6D US 2006/027581.6 A1 Dec. 7, 2006 METHODS FOR DENTIFYING DRUG compounds and are useful components of an overall candi PHARMACOLOGY AND TOXCOLOGY date evaluation strategy, the predictions must be borne out in experimentation. There has also been adaptation of specific CROSS-REFERENCE TO RELATED biochemical and cell based assays to address general phar APPLICATION macological and toxicological properties (e.g., p450 assays, hepatic enzyme activation, etc.). However many of these 0001. This application claims priority to U.S. Provisional assays have proven difficult to scale and therefore have Patent Application No. 60/687.966, filed on Jun. 7, 2005 the limited scope in terms of the number of compounds that can entire contents of which is incorporated by reference. be assessed. GOVERNMENT LICENSE RIGHTS 0007. In addition, numerous commercial efforts to lever age gene expression analysis for predictive pharmacology 0002 The U.S. Government has a paid-up license in this and toxicology, as well as biomarker discovery have invention and the right in limited circumstances to require emerged in recent years. In general, these programs typically the patent owner to license others on reasonable terms as involve the use of commercial large scale or whole genome provided for by the terms of DAMD17-03-1-0516 awarded microarrays coupled to compound testing in animal models. by The Department of Defense(DOD) Breast Cancer Two major areas of application for gene expression microar Research Program. rays are (1) pharmacogenomics, the use of gene expression FIELD OF THE INVENTION technologies to delineate the inherited factors influencing drug concentrations and/or effects among individuals or 0003. The invention relates to ex vivo methods for iden populations and (2) toxicogenomics, the use of gene expres tifying or predicting drug pharmacology and toxicology in sion technologies to identify responses to toxicant exposure Vivo and for identifying biomarkers using a microarray and variation in population response. In practice, these and/or cell-based assay. classifications represent a continuum of applications whose main goals are to identify the right medicine for the right BACKGROUND OF THE INVENTION patient: personalized medicines. Although there has been 0004 Preclinical testing of drug pharmacology and toxi significant interest in these applications since microarrays cology is generally based on the results from a series of first appeared in the mid 1990s, clinical applications are only biochemical, cellular and animal studies that together are beginning to emerge. In the last few years several examples used to select the most promising drug candidates for of personalized medicines have been approved for sale, development. While some of these screens are reused for including Herceptin (Genentech1; trastuzumab) for treat many therapeutic programs (e.g., mouse toxicity, p450 ment of breast tumors overexpressing HER2, Gleevec assays) others assess specific biological endpoints that are (Novartis; imatinib) for lymphoma, and Erbitux (ImClone not portable outside of a specific therapeutic area (e.g., Systems, Bristol-Myers Squibb and Merck KGaA; cetux insulin Secretion from pancreatic beta cells). These studies imab), a colorectal cancer treatment. Each of these repre can take years to complete at significant cost to the industry sents examples in which development was based at least in and are often poor indicators of the actual efficacy and safety part on biomarkers identified by gene expression analysis or of drugs in humans. that rely on pharmacogenomic testing to identify responsive patients. Iconix Pharmaceuticals, Inc., Icoria, Inc., Gene 0005 One of the most significant problems in drug Logic, Inc., and Curagen Corp. are also major competitors in discovery and development is the attrition of compounds. this arena. Each has developed toxicogenomic offerings Currently, 80% of compounds entering Phase 3 trials survive based on screening known drugs and toxins in animals and to become a marketed drug. The attrition rates in earlier coupling that information with traditional histopathological stages of development are significantly worse, leading to analysis to identify biomarkers of specific toxicity and fewer than 1 in 10,000 early stage candidates making it to efficacy. Icoria's business couples whole genome expression market. Estimates are that the development cost of every analysis with metabolic profiling to identify predictive drug includes -S70 million US dollars for candidates that markers as well as Straight forward toxicogenomic screening fail to make it to market. Moreover, reducing attrition by a through an interaction with the National Institutes of Envi single percentage point or enabling compounds destined to ronmental Health Science (NIEHS). Of relevance to this fail to be eliminated from development earlier are estimated application and these efforts are U.S. Pat. Nos. 6.801,859, to lead to savings in excess of hundreds of millions of US 6,635,423 and 6,852,845. Patient stratification based on dollars in development costs for a given drug. Consequently, genetic variation analysis is now becoming part of clinical there is significant interest in the pharmaceutical industry for trial design and treatment choice, especially with respect to technologies that will allow companies to predict which variations in drug metabolism enzymes. Although these compounds are likely to be the most safe and effective. examples provide some useful information, biomarker dis 0006. As the pharmaceutical industry has struggled to covery, patient stratification and development of personal increase the efficiency of their drug pipelines, a number of ized
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