Multiplex biomarkers on the rise	April 2009

Michael Spain, M.D., chief medical officer at Rules-Based Medicine Inc., an Austin, Texas-based biomarkers testing laboratory, answered questions from R&D Directions about the emergence of multiplex biomarker assays in drug development.

Q: How does the use of multiplex biomarker assays in drug development align with the current motivations of leading pharmaceutical companies?

A: In the current economic environment prioritizing and selecting the right drug candidates is of paramount importance to pharmaceutical companies. Consequently, demand for multiplex assays is driven in part by the advantages they provide in terms of evaluating the toxicity and efficacy effects of compounds. With improved information, companies can make better decisions regarding drug candidate advancement. 

In a recent project with VentiRx, we combined our HumanMAP biomarker assays with our TruCulture system for ex-vivo immune system monitoring to establish that VentiRx’s Phase I dosage protocol was consistent with their preclinical results. This type of approach can reduce risk and save time and money in drug development.

Q: What is the market demand for multiplex assays?

A: Demand is also based on pharmaceutical companies’ interest in early diagnosis. For example, in the past many Alzheimer’s drugs have failed, but some researchers believe that had their drug been used in the earlier stages of the disease it might have been more successful.  However, the lack of an early diagnostic for Alzheimer’s precludes testing this theory. Use of biomarker-based multiplex assays may offer a pathway for early diagnosis and enable pharmaceutical companies to improve drug utility.

Clinical trials present a significant expense for pharmaceutical companies, and multiplex biomarker assays may help to reduce costs by replacing clinical endpoints with biomarker endpoints. For instance, a comprehensive Alzheimer or cardiovascular trial might require five to ten years to complete under traditional circumstances and monitoring techniques, but that timeframe could be considerably compressed by using biomarker measurements to evaluate the performance of the drugs.

Q: What are some notable advances in biomarker detection technologies?

Within the pharmaceutical and diagnostics industries, companies have spent significant time and money searching for single biomarkers to help in disease characterization and early diagnosis. While there have been a few successes, single biomarkers of disease are simply not prevalent. 

The evolution of multiplex assays represents a primary advance, whether dealing with proteins or nucleic acids. Running one test one at a time can be labor intensive and therefore expensive. In addition, it is difficult to achieve high diagnostic sensitivity and specificity with single biomarkers.  If you try to raise sensitivity, you often end up with an increase in false positives. Multiplex assays are efficient and allow you to raise sensitivity and specificity at the same time. We recently introduced a Human KidneyMAP that includes 16 biomarkers. This panel offers a dramatic improvement in the early detection of kidney damage over the singleplex creatinine test.

At RBM we have nearly 200 human immunoassays on a validated diagnostic platform. In clinical projects with our customers and our internal diagnostic initiatives, we can use the full panel of assays to discover new patterns, typically based on 10-20 biomarkers. We then quickly combine those assays for efficient processing of late stage clinical trial samples or for diagnostic validation studies. We believe our biomarker discovery and validation platform, which utilizes the Luminex multiplex technology, is a powerful tool for drug research and diagnostic biomarker panel discovery.
 
Q: Can you describe RBM’s current biomarker validation project of blood-based protein assays, including the test intended to improve diagnosis of schizophrenia?

A In terms of objective diagnostics, psychiatric conditions are among the least served areas in medicine. Today there are no blood tests for these conditions. As you know, schizophrenia is a devastating and costly condition that places a substantial burden on individuals, families and healthcare system. Because it is diagnosed almost solely through clinical evaluation it is not unusual for patients to be diagnosed only after they begin to suffer psychotic episodes or to be misdiagnosed due to mimic conditions. As a result, patients may go untreated or be inappropriately treated. We want to provide a family of objective tests to serve the psychiatry market. We are exploring applications ranging from early detection to therapeutic monitoring and believe the impact on care will be dramatic.

To develop a blood test for schizophrenia, RBM is combining its unique diagnostic validation platform and extensive portfolio of biomarker assays with novel biomarker technology from our partner Psynova Neurotech. Our platform enables us to screen large numbers of samples for large numbers of analytes for any disease to identify a smaller number of biomarkers that correlate to the targeted disease.

Q: What has your company learned from this study?

A: One of the major things we’ve learned thus far is that finding biomarkers associated with a psychiatric condition such as schizophrenia is not as difficult as one might expect. When you’re looking at a disease like Alzheimer’s, which is found in older individuals, you are likely to face co-morbid conditions such as diabetes and cardiovascular disease, which makes it more difficult to sort things out. In contrast, schizophrenia often occurs in young people, a population that is not subject to co-morbidity.  Consequently, biomarker discovery is more straightforward.

Q: How does RBM’s MAP technology platform work?

A: Our large-scale profiling uses Luminex’s multiplex technology, which in essence amounts to miniaturized ELISA’s. Typically, large-scale profiling utilizes mass spectrometry, but so far success has been limited in relation to the amount of money that has been spent. Mass spectrometry is not highly sensitive so it misses a lot of proteins and on first pass is not very useful in identifying the proteins. People like our quantitative approach. 

Q: How is the work of various biomarker collaborations between industry, academia, and government helping improve efforts in both validating surrogate markers as well as increasing disease-target understanding in drug discovery?  

Collaboration is important in our industry.  One area that has received a lot of attention and funding is the Critical Path Initiative, which is a collaborative effort between industry and the FDA to pool resources for drug safety and efficacy testing so pharmaceutical companies wouldn’t have to reinvent the wheel. 

Our Rat KidneyMAP for toxicity screening resulted from a Critical Path Initiative collaboration between Novartis and the FDA, through the Predictive Safety Testing Consortium. Novartis performed biomarker discovery and contracted with us to develop the assay and test over 4,000 samples. The Rat KidneyMAP utilizes entirely different markers than traditional panels for evaluation of renal toxicity, and it is more sensitive and specific.

Another example of collaboration is the Biomarker Consortium, which brings together academia and government in a coordinated effort to study biomarkers. In Europe there is the Innovative Medicines Initiative, which is involves industry, government and academia. Over the next ten years it will fund 1 billion euro worth of consortiums in areas such as psychiatry and drug safety.