Cablecv021909

Updated 02/09

Edward E. Cable, Ph.D. 17239 Grandee Place San Diego, CA 92128

(858) 603-0855 (c) [email protected] SUMMARY

Highly experienced, intensely creative scientist and emerging leader, with a demonstrated record of sustained success in drug discovery and academic science. A collaborative investigator who enjoys the challenge of identifying and implementing novel research projects with the potential to address unmet medical needs. An engaging communicator, equally comfortable interacting with academic and pharmaceutical scientists, other functional specialists – including physicians – and executives.  

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Experienced and developmentallyoriented project manager Evaluation, selection and implementation of intellectual property opportunities Established multiple academic and business partnerships; experienced in Contract Research Organization (CRO) management

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Successful in acquiring funding from NIH and other sources Preclinical team leadership and clinical development team participation Published author of more than 30 peer-reviewed manuscripts, and numerous reports and presentations

Employment History Scientific Investigator 2002 - 2009 Metabasis Therapeutics La Jolla, CA 92037 Metabasis is a biopharmaceutical company focused on the discovery, development and commercialization of novel drugs by applying its proprietary technologies, scientific expertise and unique capabilities for targeting the liver and liver pathways. Examples of accomplishments and responsibilities at Metabasis Leadership/service Project Leader, Liver-targeted thyroid hormone receptor agonist for the treatment of elevated LDL cholesterol  Managed project to identify viable clinical candidate, MB07811, within 4 years Project initiated Ql 2003, FIH October 20, 2006  Managed team of up to 8 scientists to evaluate compounds from lead selection through advanced pharmacology and safety studies  Evaluated, selected and worked with CROs to perform studies for MB07811 pre-clinical safety and efficacy

Edward Cable

Curriculum Vitae

Project leader: undisclosed peripheral obesity target and lipid modification targets  Implemented a high throughput screening assay and obtained target validation for the obesity target  Implementation of in vitro screens for reverse cholesterol transport Designed and implemented a company-wide wellness program to encourage non-athletes to start and continue a voluntary wellness program. Program achieved more than 75% voluntary participation. Communication Co-authored 5 published peer-reviewed manuscripts and 6 meeting presentations disclosing MB07811 for the treatment of elevated LDL cholesterol, obesity and hepatic steatosis Authored the patent application for the use of synthetic thyroid receptor agonists as a treatment for hepatic steatosis Authored key portions of the pre-clinical biology section of the MB07811 IND Authored numerous internal study reports and source documents Identified, authored and initiated a novel project (undisclosed target) and authored one novel project proposal per year Technical Skills Broad based in vitro and in vivo pharmacology skills Functional cell-based assays for the analysis of inhibitors and activators including advanced in vitro pharmacology for GPCRs Designed and implemented a novel cost-effective, predictive in-vivo pharmacology screen, increasing throughput by more than 5-fold, and the murine radiometric reverse cholesterol transport assay (Rader model) Designed and implemented sub-chronic safety studies, pharmacokinetic (PK) and pharmacodynamic (PD) studies in both small and large animals Performed complex statistical analyses of continuous, non-continuous and categorical data using JMP software (SAS Corporation), Sigma Plot, Basic pharmacokinetic analysis (WinNonLin-Pharsight, Inc.), and lipomic data analysis Collaborations Identified, initiated and completed collaborations with CRO’s and academic partners MPI research – Mattawan, Michigan  Key single rising and repeat rising dose PK and efficacy data in primates in support of MB07811 MDS Pharma Services – France and Singapore  Key selectivity and mutagenicity studies in support of MB07811 Core Imaging Facility – VA Hospital, San Diego  Utilized EM facilities for analysis of hepatocyte ultrastructure Lipomics Technologies – Sacramento  Provided publication quality lipomic data (see reference 31)

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Edward Cable

Curriculum Vitae

Steven I. Shedlofsky, M.D. – Professor of Internal Medicine, University of Kentucky and Head of the Hepatitis C treatment program for Kentucky Department of Corrections  Provided insights into undisclosed program and HCV programs

Postdoctoral Fellow through Assistant Professor 1994 –2002 Department of Microbiology and Immunology Penn State College of Medicine Milton S. Hershey Medical Center Hershey, PA Penn State College of Medicine is the premier teaching and research hospital in central Pennsylvania and the Medical School of Penn State University. Examples of accomplishments and responsibilities at Penn State-HMC Communication Authored/co-authored 10 published peer-reviewed manuscripts and 3 funded grant applications Successfully secured and maintained external funding for academic position at >80% for the full duration of tenure Taught sections of graduate classes on oxidative and cellular damage Presented novel academic work at national and international conferences via oral presentations and posters Technical Skills Developed and implemented tissue culture methods for both primary cells and immortalized and transformed cell lines and engineered cell lines Implemented microscopy methods including transmission electron microscopy and immuno-EM, scanning laser confocal and deconvolution microscopy and time-lapse phase contrast microscopy performed over the course of hours or days Designed an RNA gel shift assay to detect protein/RNA interactions within the ALA synthase mRNA used to identify protein binding motifs within the ALA synthase mRNA and identified a novel RNA binding motif in the 3’ end of the translated portion of the ALA synthase mRNA Assisted with the development and analysis of a novel cellular HBV assay and the characterization of HBV antivirals Lead statistician in the analyses of novel antivirals using JMP (SAS) and GraphPad (Prism) Assisted with the design and implementation of viral gene transfer vectors and methods to primary hepatocytes and cell lines Designed experiments and analyzed genomic data from iron loaded and viral infected cells identifying novel genes regulated by iron in the absence of an oxidative stress

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Edward Cable

Curriculum Vitae

Collaboration Established collaborative academic efforts among PI’s from three different departments leading to the receipt of Program Project funding (5P01DK053430) >$1M/4 years: Harriet Isom, Michael Chorney, James Conner, and Mel Billingsley Graduate Student to Postdoctoral Research Associate 1990- 1994 Department of Biochemistry and Molecular Biology and Division of Digestive Disease and Nutrition University of Massachusetts Medical Center, Worcester, MA Herbert L. Bonkovsky, M.D., Advisor The University of Massachusetts Medical Center was established in 1970 and has the mission of conducting interdisciplinary research. Examples of responsibilities and accomplishments at UMass Authored/co-authored 17 peer reviewed publications Implemented tissue culture methods for both primary cells and transformed cell lines Implemented protein expression, purification and analysis methods Assisted with the development of a novel nuclear transcription assay Developed iron standards for validation of an non-invasive hepatic iron content assay using MRI Statistician for pathology data evaluating effects of hepatic iron content in response rates of HCV infected patients treated with interferon and ribavirin

Education and Professional Development Continuing education includes: Leadership and supervisory classes and workshops, harassment prevention training, technical writing, negotiation, project management Formal Education University of Massachusetts Medical Center Herbert L. Bonkovsky, M.D., Advisor

Ph.D. Biochemistry

Thesis Regulation of -aminolevulinic acid synthase and heme oxygenase in cultured chick embryo liver cells: Synergistic induction of both enzymes by glutethimide and iron and repression of -aminolevulinic acid synthase by metalloporphyrins and heme. Emory University

Graduate Program Biochemistry

Grove City College

B.S. Chemistry

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Edward Cable

Curriculum Vitae

Awards Metabasis, First in Human MB07811 Biology Project Leader American Liver Foundation Liver Scholar Award November, American Gastroenterology Association Student Research Award Runner-up Senior Research Award, Grove City College Past Grant Funding July 1, 2000 -February 2002 American Liver Foundation - $150k February 1, 1997 - January 31, 1998 Heme-Mediated Instability of ALA synthase mRNA. National Institute of Diabetes and Digestive and Kidney Diseases grant F32 DK09609 - $45k November 1, 1994 - October 31, 1996 Regulation of ALA Synthase in Rat Hepatocyte Cell Lines. National Institute of Diabetes and Digestive and Kidney Diseases grant F32 DK09205 - $75k

Professional Society Membership American Association for the Study of Liver Diseases December 2001- present Full Papers 1. Cable, E., Y. Greene, J. Healey, C.O. Evans and H. Bonkovsky (1990) Mechanism of synergistic induction of hepatic heme oxygenase by glutethimide and iron: studies in cultured chick embryo liver cells. Biochemical Biophysical Research Communications 168:176-181. 2. Cable, E.E., J.F. Healey, Y. Greene, C.O. Evans and H.L. Bonkovsky (1991) Synergistic induction of -aminolevulinate synthase by glutethimide and iron: relationship to the synergistic induction of heme oxygenase. Biochimica Biophysica Acta 1080:245-251. 3. Bonkovsky, H.L., E.E. Cable, J.W. Cable, S.E. Donohue, E.C. White, Y.J. Greene, R.W. Lambrecht, K.K. Srivastava and W.N. Arnold (1992) Porphyrogenic properties of camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh). Biochemical Pharmacology 43:23592368.

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Edward Cable

Curriculum Vitae

4. Srivastava, K.K., E.E. Cable, S.E. Donohue and H.L. Bonkovsky (1993) Molecular basis for heme-dependent induction of heme oxygenase in normal hepatocytes with demonstration of acquired refractoriness to heme. European Journal of Biochemistry 213:909-917. 5. Cable, E.E., J.W. Cable and H.L. Bonkovsky (1993) Repression of hepatic aminolevulinate synthase by heme and metalloporphyrins: relationship to inhibition of heme oxygenase. Hepatology 18:119-127. 6. Srivastava, K.K., E.E. Cable and H.L. Bonkovsky (1993) Purifying nascent mRNA from nuclear run-on assays using guanidinium isothiocyanate. Biotechniques. 15:226-227. 7. Cable, J.W., E.E. Cable and H.L. Bonkovsky (1993) Induction of heme oxygenase in intestinal epithelial cells: Studies in Caco-2 cell cultures. Molecular and Cellular Biochemistry 129: 93-98. 8. Cable,E.E., J.A. Pepe, N.C. Karamitsios, R.W. Lambrecht, and H.L. Bonkovsky (1994) Differential effects of metalloporphyrins on mRNA levels of aminolevulinate synthase and heme oxygenase: studies in cultured chick embryo liver cells. Journal of Clinical Investigation 94:649-654. 9. Russo, S.M., J.A. Pepe, E.E. Cable, R.W. Lambrecht and H.L. Bonkovsky (1994) Reduction of -aminolevulinic acid synthase by metalloporphyrins and heme. European Journal of Clinical Investigation 24:406-415. 10. Cable,E.E., J.A. Pepe, S.E. Donohue, R.W. Lambrecht and H.L. Bonkovsky (1994) Porphyrinogenicity of RU-486: studies in cultured chick embryo liver cells. European Journal of Biochemistry 225:651-657. 11. Clifford, B.D., D. Donahue, L. Smith, E. Cable, B. Luttig, M. Manns and H.L. Bonkovsky (1995) High prevalence of auto-immunity in patients with chronic hepatitis C. Hepatology 21: 613-619. 12. Russo, S.M., J.A. Pepe, S.E. Donohue, E.E. Cable and H.L. Bonkovsky (1995) Tissue distribution of zinc-mesoporphyrin in rats: relationship to inhibition of heme oxygenase. Journal of Pharmacology and Experimental Therapeutics 272:766774. 13. Barton, A.L., B.F. Banner, E.E. Cable and H.L. Bonkovsky (1995) Distribution of iron in the liver predicts the response of chronic hepatitis C infection to interferon therapy. American Journal of Clinical Pathology 103: 419-424. 14. Banner, B.F., A.L. Barton, E.E. Cable, L. Smith, H. Bonkovsky (1995) A detailed analysis of the knodell score and other histologic parameters as predictors of response to interferon therapy in chronic hepatitis C. Modern Pathology 8:232-238.

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Edward Cable

Curriculum Vitae

15. Cable, E.E., J.A. Pepe, S.E. Donohue, O.S. Gildemeister, R.W. Lambrecht and H.L. Bonkovsky (1996) Regulation of -aminolevulinate synthase mRNA: Modulation of mRNA half-lives is required for induction and repression. European Journal of Biochemistry 240:112-117. 16. Cable, E.E., J.A. Pepe, O.S. Gildemeister, R.W. Lambrecht and H.L. Bonkovsky (1997) Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: Evidence for a protein-mediated response. Molecular and Cellular Biochemistry 169:13-20. 17. Cable, E.E. and H.C. Isom (1997) Exposure of primary rat hepatocytes in long-term DMSO culture to selected transition metals induces hepatocyte proliferation and formation of duct-like structures. Hepatology 26:1444-1457. 18. Cable, E.E., J.R Connor and H.C. Isom (1998) Accumulation of iron by primary rat hepatocytes in long term culture: Incorporation of low concentrations of nontransferrin bound forms of iron. American Journal of Pathology 152:781-792. 19. Cable, E.E. and H.C. Isom (1999) Metabolism of 3,5,5-trimethylhexanoylferrocene by rat liver: Release of iron from 3,5,5-trimethylhexanoyl -ferrocene by a microsomal, phenobarbital-inducible cytochrome P450. Drug Metabolism and Disposition 27:255-260. 20. Ten Elshof, A.E., G.M. Brittenham, K.A Chorney, M.J. Page, G. Gerhard, E.E. Cable, M.J. Chorney (1999) IELs drive TNF- responsiveness to intestinal iron challenge: Relevance to hemochromatosis. Immunological Reviews 167: 225 - 234. 21. Bonkovsky, H.L., R.B. Rubin, E.E. Cable, A. Davidoff, T.H. Pels Rijcken and D.D. Stark (1999) Nonivansive estimation of hepatic iron concentration by magnetic imaging techniques. Radiology 212: 227-234. 22. Cable, E.E., T.G. Miller and H.C. Isom (2000) Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines: -aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms. Archives of Biochemistry and Biophysics 384:280-295. 23. Malecki EA, E.E. Cable, H.C. Isom and J.R. Connor (2002) The lipophilic iron compound TMH-ferrocene ([3,5,5-trimethylhexanoyl] ferrocene) increases iron concentrations, neuronal L-ferritin, and heme oxygenase 1 in brains of BALB/c mice. Biological Trace Elements Research 86:73-84. 24. Cable, E.E., B.J. Kuhn and H.C. Isom (2002) Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells: Induction of aminolevulinic synthase mRNA and protein by okadaic acid. DNA Cell Biology 21:323332.

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Curriculum Vitae

25. Abdelhamed, A.M., C.M. Kelley, T.G. Miller, P.A. Furman, E.E. Cable and H.C. Isom (2003) Comparison of anti-hepatitis B virus activities of lamivudine and clevudine by a quantitative assay. Antimicrobial Agents Chemotherapy 47:324-336. 26. Bilello, J.P., E.E. Cable and H.C. Isom (2003) Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes. American Journal of Pathology 162:1323-1338. 27. Bilello, J.P., E.E. Cable, R.L. Myers and H.C. Isom (2003) Role of paracellular junction complexes in baculovirus-mediated gene transfer to nondividing rat hepatocytes. Gene Therapy 10:733-49. 28. Erion, M.D. , E.E. Cable, B.R. Ito, , H. Jiang, J.M. Fujitaki, P.D. Finn, B-H. Zhang, J. Hou, S.H. Boyer, P.D. van Poelje, and D.L. Linemeyer (2007) Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proceedings of the National Academy of Sciences USA 104: 15490-15495. 29. Fujitaki J.M., E.E. Cable, B.R. Ito, B.H. Zhang, J. Hou , C. Yang, D.A. Bullough, J.L. Ferrero, P.D. van Poelje, D.L. Linemeyer and M.D. Erion (2008) Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist. Drug Metabolism and Disposition 36: 2393-2403. 30. Boyer, S.H., H.J. Jiang , J.D. Jacintho, M.V. Reddy, H. Li, W. Li, J.L. Godwin, W.G. Schulz, E.E. Cable, J. Hou, R.R. Wu, J.M. Fujitaki, S.J. Hecker and M.D. Erion (2008) Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs Journal of Medicinal Chemistry 51: 7075–7093. 31. Cable, E.E., .D. Finn, J.W. Stebbins, J. Hou, B.R. Ito, P.D. van Poelje, D.L. Linemeyer, and M.D. Erion (2009) Reduction of hepatic steatosis in rats and mice following treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 49: 407-417. 32. Ito, B.R., B.H. Zhang, E.E. Cable, X. Song, J.M. Fujitaki, D.A. Mackenna, C.E. Wilker, B. Chi, P.D. van Poelje, D.L. Linemeyer and M.D. Erion (2009) Thyroid hormone- receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs, and monkeys British Journal of Pharmacology 156: 454-465.

Patents and Patent Applications 1. Cable, E.E. and M.D. Erion PCT/US2006/020610 (WO/2006/128058) Thyromimetics for the treatment of fatty liver diseases

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Edward Cable

Curriculum Vitae

Selected Recent Abstracts (from a total of 36) 1. Linemeyer, D.L., E.E. Cable, B.R. Ito, H. Jiang, J.M. Fujitaki, P.D. Finn, B. Zhang, J. Hou, S.H. Boyer, P.D. van Poelje and M.D. Erion. Liver-targeted thyroid hormone receptor agonist reduces cholesterol and triglyceride levels with an improved therapeutic index. Endocrinology P3-566, 2007. 2. Ito, B.R., E.E. Cable, S.H. Boyer, H. Jiang, B. Zhang, P.D. Finn, X. Song, P.D. van Poelje, D.L. Linemeyer and M.D. Erion. A liver-targeted thyroid receptor agonist prodrug. Cholesterol lowering activity in a variety of animal models. Endocrinology P3-567, 2007. 3. Linemeyer, D.L., P.D. van Poelje, E.E. Cable, B.R. Ito, D. MacKenna and M.D. Erion. MB07811, a liver-targeted prodrug of a novel thyroid hormone receptor agonist, lowers plasma cholesterol in cynomolgus monkeys as effectively as atorvastatin. Diabetes 0565-P, 2007. 4. Hou, J., I.S. Belka, R. Wu, P.D. Finn, J. Li, E.E. Cable, B.R. Ito, P.D. van Poelje, D.L. Linemeyer, M.D. Erion MB07811, a liver-targeted prodrug of a novel thyroid hormone receptor agonist, does not cause hyperglycemia in Sprague-Dawley rats or diet induced obese mice. EASD 1195, 2007. 5. Boyer, S.H., H. Jiang, J.D. Jacintho, M.V. Reddy, H. Li, W. Li, W.G. Schulz, J.L. Godwin, S.J. Hecker, E.E. Cable, B.R. Ito, J.M. Fujitaki, P.D. Finn, B-H. Zhang, J.Hou, P.D.van Poelje, D.L.Linemeyer, and M.D. Erion. MB07811: A liver-selective thyroid receptor agonist prodrug for the treatment of hyperlipidemia American Chemical Society MEDI20, 2007. 6. Cable, E.E., , P.D. Finn, J. Li, J.W. Stebbins, M.P. Haughey, J. Hou, B.R. Ito, P.D. van Poelje, D.L. Linemeyer, and M.D. Erion MB07811, a HepDirect prodrug of a liver-targeted thyroid hormone receptor (TR) agonist, and other synthetic non-livertargeted TR agonists, but not T3, reduce hepatic steatosis Hepatology 369349, 2007. 7. Potter, S.C., P.D. van Poelje, J. Gomez-Galano, E.E. Cable, J.R. Parise, M.L. McCaleb, D.L. Linemeyer, and M.D. Erion Eight week treatment of db/db mice with a small molecule antagonist of the glucagon receptor lowers HbA1c and plasma triglyceride levels without α-cell hyperplasia EASD 2008, PS 083.

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