Integrating Proteomic Biomarkers Into Personalized Drug Dosing

Jon Klein, M.D., Ph.D.University of Louisville

Pharos Medicine

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Goals

• Define the problem of anemia in end-stage renal disease (ESRD).

• Review the rise of recombinant erythropoietin (rEPO) as a therapy.

• Review the emerging doubts about rEPO and subsequent changes in dosing.

• Describe proteomic data of biomarkers of rEPO response.

• Describe the merger of biomarkers with a model predictive control tool to adjust rEPO dose.

The Golden Age of Anemia Treatment

• The WHO defines anemia as a Hgb < 13 in males and < 12 in premenopausal females

• By this definition > 90% of patients with kidney disease are anemic

• Beginning in 1989, kidney patients began receiving FDA approved rEPO.

• EPO use in cancer and HIV patients soon followed

The Golden Age of Anemia Treatment

The Golden Age Begins to End

N Engl J Med. 1998 Aug 27;339(9):584-90.

Nl Hct = 42Low Hct = 30

N Engl J Med 2006;355:2085-98.

ConclusionsThe 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.

The Golden Age EndsWARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCEChronic Kidney Disease:

• 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).

• No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.

• Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).

“Clinicians should use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions”

Clinicians’ Response

• EPO weekly dose fell 12.5% in 2 years.• Hgb targets are shifted from 10-13 to 10-11

g/dl

Discovery of EPO Response Biomarkers

Hypothesis

• The plasma proteome may distinguish between patients that are resistant and sensitive to RhEpo

Patient Population

Good Responder Poor Responder p-value

Gender (m/f) 20/15 19/16 0.6

Hemoglobin (g/dL) 11.5±0.6 11.2±1.1 0.4

ESA Dose

(U/treatment)

1467±673 8392±5833 <0.001

Average ERI 0.11±0.036 0.87±0.51 <0.001

Albumin (g/dL) 3.9±0.3 3.8±0.3 0.3

Ferritin 767±353 781±416 0.9

Tsat (%) 30.5±7.9 26.4±16.5 0.4

Analytical workflow for peptide separation and identification

Peptide ExtractionPeptide Quantification

Peptide Separation1D RP capHPLC

Robotic Fraction CollectionMALDI Plate Spotting

Precursor Ion Peak ListSubsequent TOF/TOF MS

Computer-Aided ModelingBioinformatics

Assignment of Peptide Identity

Results

Peptide and Protein Biomarkers

Sensitivity of the Candidate Biomarkers

Applying Intelligent Control to EPO Dosing

Standardized EPO Protocol

EPO DOSE VS RESPONSE

Model Predictive Control

ModelDose Optimizer

EPO Hb

Patient

0 1 2 3Months

12

10

Hb

EPO Dose IncrementTarget RangeMinimization

Pharmacodynamic ResponseModel

Multiple Model Predictive Control (MMPC) System for Anemia Management

MMPC Results

Apr 2011 May 2011 Jun 2011

69.0

59.0

51.2

73.8 74.4 74.4

Percent Hgb 10-12Protocol SAM

Combining EPO Biomarkers and MMPC

• Use serum biomarker of EPO resistance to “prime” the MMPC anemia manager

Epo Resistance vs. OSMR

0 10 20 30 40 50 600

20000400006000080000

Dose

0 10 20 30 40 50 605.0

7.0

9.0

11.0

Hemoglobin

0 10 20 30 40 50 600

20000400006000080000

Dose

Biomarker Incorporation for Dosing

0 10 20 30 40 50 605.0

7.0

9.0

11.0

Hemoglobin

Conclusions

• The treatment of anemia in ESRD remains challenging.• Concerns about unbridled EPO treatment have

emerged.• Proteomic analysis revealed serum biomarkers of EPO

resistance and susceptibility• The use of intelligent control methods (MMPC)

provided personalized EPO dosing with results superior to standard protocols

• The combination of proteomic biomarkers and MMPC shows promise in guiding individualized EPO dosing.

“Art is I, Science is we.” Claude Bernard

• Louisville– Michael Merchant– Michael Brier– Adam Gaweda

• The Ohio State Univ. – Brad Rovin

• Funding– NIH, DVA, DOE – KY Research Challenge Trust