Integrating Proteomic Biomarkers Into Personalized Drug Dosing <br />Jon Klein, M.D., Ph.D.<br />University of Louisville<...
Disclosure Verification for:  <br />Name:  Jon Klein, MD PhD<br />The presenter listed above:<br />___ Does not have any s...
Goals	<br />Define the problem of anemia in end-stage renal disease (ESRD).<br />Review the rise of recombinant erythropoi...
The Golden Age of Anemia Treatment<br />The WHO defines anemia as a Hgb < 13 in males and < 12 in premenopausal females<br...
The Golden Age of Anemia Treatment<br />
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 />
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 comp...
The Golden Age Ends<br />WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, ...
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 />
Discovery of EPO Response Biomarkers<br />
Hypothesis<br />The plasma proteome may distinguish between patients that are resistant and sensitive to RhEpo<br />
Patient Population<br />
Peptide Extraction<br />Peptide Quantification<br />Peptide Separation<br />1D RP capHPLC<br />Robotic Fraction Collection...
Results<br />
Peptide and Protein Biomarkers<br />
Sensitivity of the Candidate Biomarkers<br />
Applying Intelligent Control to EPO Dosing<br />
Standardized EPO Protocol<br />
EPO DOSE VS RESPONSE<br />
Model Predictive Control<br />Model<br />Dose Optimizer<br />EPO<br />Hb<br />Pharmacodynamic Response<br />Model<br />EPO...
Multiple Model Predictive Control (MMPC) System for Anemia Management<br />
MMPC Results<br />
Combining EPO Biomarkers and MMPC<br />Use serum biomarker of EPO resistance to “prime” the MMPC anemia manager<br />
Epo Resistance vs. OSMR <br />
Biomarker Incorporation for Dosing	<br />
Conclusions<br />The treatment of anemia in ESRD remains challenging.<br />Concerns about unbridled EPO treatment have eme...
“Art is I, Science is we.”                                       Claude Bernard<br />Louisville<br />Michael Merchant<br /...
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  • Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)4 and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)
  • The standard control protocol was based on an interpretation of national anemia guidelines from The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (5) and the package insert for EPOGEN
  • For this example I am using OSMR as the biomarker of choice since the OSMR data seem to correlate much nicer with Epo Resistance Index (ERI), hence are more illustrative. Here you see the data plot of ERI vs. total OSMR abundance with a nice “exponential” curve fit to show the relationship between the two. Using this fit, I was able to calculate Epo responsiveness for different levels of OSMR abundance (not shown here). ERI = EPO Dose/Hgb 1 month later
  • This is hypo-responder simulation when no OSMR value is provided at the beginning
  • Klein

    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>

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