Acute Kidney Injury (AKI) Biomarker Program

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Introduction
The aim of this program at Pacific Biomarkers Inc. (PBI) is to assess organ injury occurring because of specific toxic effects of drugs that are in development and that could prevent their approval. This will avert injury to patients that would have been treated by drugs whose toxicity would fail to be detected by current methods and will further reduce healthcare costs by early recognition that a drug is not safe as the result of drug-induced toxic effects. The latter is expected to speed up drug development by 1 – 3 years. Current costs related to the development of a drug, from discovery to the final approval, are estimated to be about $1 billion. Drug-induced toxicity accounts for 30% of all drug failures prior to reaching the market, and the sooner this toxicity is discovered, the sooner further costly studies could be stopped. PBI’s AKI biomarker program has the potential to diagnose toxic drug effects that currently are being missed in clinical trials.

A key strategic goal for PBI is to provide pharmaceutical and biotech companies with services for testing robust novel biomarkers that have undergone thorough analytical validation and clinical qualification to diagnose early organ injury. This work is taking place in response to FDA-initiated recommendations for streamlining and improving drug development outcomes as outlined in the Critical Path Initiative through guidance from the Predictive Safety Testing Consortium (PSTC) and the Health and Environment Sciences Institute (HESI). The anticipated qualification of organ injury biomarkers will also demand development of stringent standardization procedures (e.g., consistency of test accuracy, precision, and sensitivity). During the past 20 years PBI has acquired extensive experience in biomarker standardization as a member of the Cholesterol Reference Method Laboratory Network.

AIM
The first initiative in PBI’s safety biomarker program is to target biomarkers that can detect acute kidney injury with the aim of identifying the biological and analytical qualities of a set of markers that current literature and experimental evidence indicate have the greatest possibility of being used as biomarkers of treatment (drug)-induced AKI. This is being followed by a similar evaluation of markers associated with treatment-induced injury for liver and heart. PBI is currently collaborating with several clients to characterize the analytical performance of assays for these novel renal biomarkers.

PBI intends to characterize not only the analytical performance, but also the clinical performance through collaboration with clients. PBI has already characterized the analytical performance for some of the AKI biomarkers while validation of others is in progress (see Table 1). PBI is recommending the biomarkers marked by an asterisk (Table 1), as these cover both specific and global injury and the literature has shown them to be the most promising. Furthermore, these markers are recommended by the various consortia and by publications from key opinion leaders in this field.

Approach
PBI’s approach to offering AKI biomarkers will be to validate each of these using rigorous validation protocols for singlicate assays, with the expectation of generating the most robust data possible. During this process the company may be required to modify the assay methods or validate other methods. First, quality analytical performance is being sought to ensure that the data from the studies currently being initiated for evaluation of biomarker clinical utility provides a basis for choosing the best biomarkers. Once a panel of five to seven biomarkers with strong clinical performance has been selected, PBI will move forward with investigations on multiplex procedures for these biomarkers in order to reduce cost and improve testing turnaround time. Unfortunately, for many biomarkers, analytical performance deteriorates significantly during multiplexing. Therefore, PBI will give high priority to establishing excellent performance for the individual biomarkers before attempting to multiplex them. This will provide assay performance targets for use in the multiplex assay evaluation. Because the initial evaluation of biomarker clinical utility requires the best possible analytical performance, PBI is committed to find the methods and testing platforms that produce superior precision, accuracy, sensitivity and specificity. Later, in addition to multiplex immunoassay, other methods that employ the company’s LC-MS/MS capabilities will be investigated for analytical standardization and, if feasible, used in testing. The latter platform allows unsurpassed analytical performance.

Conclusions

PBI is well positioned to undertake this work because:

• Of its long standing history of establishing rigorous validation standards for esoteric biomarkers, and as it has the expertise and commitment required for initiating, developing, and validating these new renal injury biomarker assays. All of the proposed assays require well planned analytical performance evaluation before pharmaceutical companies involved in novel therapeutics can incorporate these biomarkers in their clinical trials.
• It is well suited to move the development of all of these assays to the next level of multiplexed methods following the initial validation of AKI candidates.

References

Method Key
EIA – Enzyme-Linked Immunosorbent Assay (ELISA)
ECL – Electrochemiluminescence Assay
iT – Immunoturbidimetric Assay
ND – Not Determined