RNA Biomarkers in Clinical Trials

Arguably, RNA is the earliest biological measure of disease, providing a relevant signal of disease onset or progression before observable clinical manifestations.

Historically, the ability to develop commercially viable RNA biomarkers has been hampered by the lack of standardized reagents, methods and platforms for the stabilization, processing and measurement of RNA transcripts. Over the last 10 years, Source MDx’s dedicated efforts towards addressing these challenges have resulted in the development of robust assays (Precision Profiles) that are supported by a highly standardized process of sample handling and processing, from phlebotomy (‘stick’) to statistical analysis of data (‘stat’). This process-oriented focus has made Source MDx the industry leader in translating RNA-based molecular diagnostic assays into clinically useful diagnostic tests. Source MDx’s own efforts have been supported and accelerated by the industry’s response to these same challenges. For example, PreAnalytix’s FDA approved PAXGene Blood RNA System consolidates and integrates key steps in whole blood collection as well as stabilization and purification of total RNA. Such rigorous and global process standardization is key in developing technically reliable and clinically informative RNA biomarkers.

The pharmaceutical and biotech industries are keen on the benefits – both for patients and industry – of utilizing RNA biomarkers as an integral part of drug development as well as a ‘risk-stratified’ approach to clinical trial design. The FDA and payers have suggested that the absence of validated biomarkers in clinical trials results in the inability to identify subgroups of patients that may benefit from or be harmed by a treatment.

Source MDx Precision Profile assays have demonstrated utility in a ‘risk-stratified’ approach to clinical trial design and execution. Recently, Source MDx and the Dana-Farber Cancer Institute announced that a Precision Profile for prostate cancer prognosis was able to stratify low risk castration-resistant prostate cancer (CRPC) patients from high-risk CRPC patients, suggesting a powerful tool for patient stratification in a clinical trial setting. Candidate prognostic and predictive biomarkers such as these are developed and rigorously validated using independent test and validation sets. The benefits are clear – RNA biomarkers as validated tests can be powerful tools for accelerating drug development through improved understanding of a drug candidate’s effect on individual patients and subpopulations; stratifying healthy vs. disease and responder vs. non-responder populations; conducting longitudinal evaluation of safety and efficacy profiles; developing companion diagnostics for targeted therapies; rapidly identifying new indications for approved drugs; and identifying opportunities to reposition drugs that have failed late-stage clinical trials.

The Source MDx approach
The Source MDx approach uses a simple blood draw to measure host response in cancer, autoimmune and other inflammation-related diseases. Source MDx Precision Profile assays measure RNA transcript-based gene expression primarily in whole blood, as well as tissues and other biofluids, using quantitative PCR optimized for clinical use in a commercial setting. Key to the Precision Profile is the concept of precision (repeatability and reproducibility) and calibration (closely matched amplification efficiencies) achieved through proprietary reagents (target gene primer probe sets), high performance 384-well assay plates and strict adherence to narrow permissible levels of experimental variables. By rigorously controlling all variables associated with the assay, the gene expression levels in a sample of a given biological condition can be measured and clear comparisons can be made between gene loci, biological conditions and individuals.

Precision Profiles are platform independent. Measurements across the same clinical samples have demonstrated equivalent results across a diverse range of commercially-available platforms that differ substantially in optics and mechanics, from the microfluidic Fluidigm BioMark System, to the more industry standard Roche LightCycler 480, Cepheid SmartCycler and ABI Prism 7900HT Sequence Detection System. Source MDx’s ‘platform independent approach’ offers practical advantages for strategic partners including ease of assay transfer, translating to a more time and cost effective rate of adoption and commercialization of a diagnostic test.

For more information, please visit www.preanalytix.com.

Kathy Storm is one of the key originators of Source MDx’s Precision Profile technology. As Vice President of Laboratory Services, she oversees commercial laboratory operations and technical aspects of Precision Profile assay and diagnostic test development. She received a doctorate in Cellular and Molecular Biology from the University of Arizona.