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  1. 1. Integrating Proteomic Biomarkers Into Personalized Drug Dosing <br />Jon Klein, M.D., Ph.D.<br />University of Louisville<br />Pharos Medicine<br />
  2. 2. Disclosure Verification for: <br />Name: Jon Klein, MD PhD<br />The presenter listed above:<br />___ Does not have any significant financial relationships to disclose<br />_x_ Has disclosed the following relationships:<br />__Research Grants __Speakers Bureau Patent holder x <br />__Consultant for fee<br />_x_Stock/Ownership Employment x Partnership <br />__Advisory Committee/Board ___Other<br />_x_ Has disclosed this activity will not include discussion of<br /> unapproved/investigational uses of products or devices<br />__ Has disclosed this activity will include discussion of <br />unapproved/investigational uses of products or devices<br />Was this activity Supported by an educational grant or received in-kind support? <br />__ Yes Name of Company: _X_No<br />
  3. 3. Goals <br />Define the problem of anemia in end-stage renal disease (ESRD).<br />Review the rise of recombinant erythropoietin (rEPO) as a therapy.<br />Review the emerging doubts about rEPO and subsequent changes in dosing.<br />Describe proteomic data of biomarkers of rEPO response.<br />Describe the merger of biomarkers with a model predictive control tool to adjust rEPO dose.<br />
  4. 4. The Golden Age of Anemia Treatment<br />The WHO defines anemia as a Hgb < 13 in males and < 12 in premenopausal females<br />By this definition > 90% of patients with kidney disease are anemic<br />Beginning in 1989, kidney patients began receiving FDA approved rEPO.<br />EPO use in cancer and HIV patients soon followed<br />
  5. 5. The Golden Age of Anemia Treatment<br />
  6. 6. The Golden Age Begins to End<br />NlHct = 42<br />Low Hct = 30<br />N Engl J Med. 1998 Aug 27;339(9):584-90.<br />
  7. 7. N Engl J Med 2006;355:2085-98.<br />Conclusions<br />The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life.<br />
  8. 8.
  9. 9. The Golden Age Ends<br />WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE<br />Chronic Kidney Disease: <br />• In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1). <br />• No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. <br />• Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1). <br />“Clinicians should use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions”<br />
  10. 10. Clinicians’ Response<br />EPO weekly dose fell 12.5% in 2 years.<br />Hgb targets are shifted from 10-13 to 10-11 g/dl<br />
  11. 11. Discovery of EPO Response Biomarkers<br />
  12. 12. Hypothesis<br />The plasma proteome may distinguish between patients that are resistant and sensitive to RhEpo<br />
  13. 13. Patient Population<br />
  14. 14. Peptide Extraction<br />Peptide Quantification<br />Peptide Separation<br />1D RP capHPLC<br />Robotic Fraction Collection<br />MALDI Plate Spotting<br />Precursor Ion Peak List<br />Subsequent TOF/TOF MS<br />Analytical workflow for peptide separation and identification<br />Computer-Aided Modeling<br />Bioinformatics<br />Assignment of Peptide Identity<br />
  15. 15. Results<br />
  16. 16. Peptide and Protein Biomarkers<br />
  17. 17. Sensitivity of the Candidate Biomarkers<br />
  18. 18. Applying Intelligent Control to EPO Dosing<br />
  19. 19. Standardized EPO Protocol<br />
  20. 20. EPO DOSE VS RESPONSE<br />
  21. 21. Model Predictive Control<br />Model<br />Dose Optimizer<br />EPO<br />Hb<br />Pharmacodynamic Response<br />Model<br />EPO Dose Increment<br />Target Range<br />Minimization<br />12<br />10<br />Patient<br />Hb<br />0 1 2 3<br />Months<br />
  22. 22. Multiple Model Predictive Control (MMPC) System for Anemia Management<br />
  23. 23. MMPC Results<br />
  24. 24. Combining EPO Biomarkers and MMPC<br />Use serum biomarker of EPO resistance to “prime” the MMPC anemia manager<br />
  25. 25. Epo Resistance vs. OSMR <br />
  26. 26. Biomarker Incorporation for Dosing <br />
  27. 27. Conclusions<br />The treatment of anemia in ESRD remains challenging.<br />Concerns about unbridled EPO treatment have emerged.<br />Proteomic analysis revealed serum biomarkers of EPO resistance and susceptibility<br />The use of intelligent control methods (MMPC) provided personalized EPO dosing with results superior to standard protocols<br />The combination of proteomic biomarkers and MMPC shows promise in guiding individualized EPO dosing.<br />
  28. 28. “Art is I, Science is we.” Claude Bernard<br />Louisville<br />Michael Merchant<br />Michael Brier<br />Adam Gaweda<br /><ul><li>Funding
  29. 29. NIH, DVA, DOE
  30. 30. KY Research Challenge Trust
  31. 31. The Ohio State Univ.
  32. 32. Brad Rovin</li>