AvalonRx®
Pharmaceutical Development and Clinical Biomarkers

The AvalonRx® approach also facilitates the development of clinical candidate drugs by enabling identification of pharmacodynamic markers for use in patient stratification or for drug response prediction in clinical trials. The predictive power of the AvalonRx® platform qualitatively enhances and accelerates the drug discovery and development process, and continues to make an impact after a drug candidate enters into clinical trials.

AvalonRx® characterization of biomarker responses of therapeutic candidates helps guide patient selection, drug protocol development and the monitoring of patient response.

In addition to providing an engine for the discovery of multiple types of therapeutic products, the Avalon approach directly supports advances in patient treatments.

The Avalon approach enables:

• Comprehensive molecular understanding of drug action prior to administration in patients,
• Development of biomarkers as early indicators of patient response,
• Improved design of clinical trials.

Gene responses observed in treated patients help build powerful predictors that further increase the power of the AvalonRx® engine.

Avalon has developed a pipeline of small molecule drugs for the treatment of both solid tumors and hematological malignancies. Additionally, Avalon's target discovery program has led to the identification of multiple novel candidate therapeutic antibody targets.

Our lead product candidate, AVN944, is an oral small molecule drug candidate currently in clinical trials for both hematological and solid malignancies. In addition, we recently advanced AVN944 into a Phase II trial in solid tumors.

We have identified a set of AVN944 biomarkers that correlated with activity in patient samples from a Phase I trial. In leukemia and myeloma patients, these biomarkers can be readily measured in routine peripheral blood samples. This information will prove invaluable in designing and conducting the Phase II trials.

Every step of Avalon's drug discovery, characterization and optimization process can be a source of new biomarkers or can help validate existing biomarkers. Characterization of drug activity on cells by gene expression analysis is a robust way of identifying potential biomarkers.

As markers of response, these genes, or their protein products, can be used to assess the response of patients to the drug early in clinical testing. This creates critical decision points for clinical development programs and leads to the design of more efficient clinical trials. The state of activation of these compound-responsive genes in a patient’s disease can be used to predict whether or not that patient will respond to the drug in a beneficial way. This enables us to stratify patient populations and increases the chance of showing significant clinical benefit without the need for tissue biopsies, which are often required for assaying traditional biochemical or metabolic disease markers.


References:

Jeffery W. Strovel, Tammy Lawrence, Marion Chakiath, Pachai Natarajan, Karina Zuck, Stephen Glanowski and David K. Bol Modulation of Gene Expression and Guanosine Pools by Inhibition of Inosine Monophosphate Dehydrogenase (IMPDH); correlating In vitro Cell Resistance with Biomarker Response in Patient Samples from the Phase I Trial (as PDF file) AACR Annual Meeting , April 14-18, 2007, Los Angeles, CA

Zoe Weaver, Jeffery W. Strovel, Marion Chakiath, Pachai Natarajan, Tammy Lawrence, and David K. Bol Antiangiogenic Properties of AVN944, A Potent Inhibitor of IMPDH (as PDF file) AACR Annual Meeting, April 14-18, 2007, in Los Angeles, CA

Jeffrey W. Strovel1, Marion Chakiath1, Stephen Glanowski1, Anna Glodek1, Simon Katz1, Tammy Lawrence1, Pachai Natarajan1, Karina Zuck1, Lenore Urbani2, Beverly Mitchell2, and David K. Bol1. 1Avalon Pharmaceuticals, Germantown, MD; 2Stanford Comprehensive Cancer Center, Stanford, CA. Genetic and biochemical biomarkers of IMPDH inhibition in phase I dose escalation of AVN944 for hematologic malignancies. American Association of Hematology Annual Meeting, Orlando, FL, Dec 2006.

Kathryn Strand, Hanif Khalak, Jeffrey W. Strovel, Reinhard Ebner, Meena Augustus. Expression biomarkers for clinical efficacy and outcome prediction in cancer. Pharmacogenomics, Jan;7(1):105-15 (2006).

D.K. Bol, J. Strovel, M. Douvas, P. Natarajan, Q. Zong, J. Castaneda, M. Chakiath, and B. Mitchell. "Genetic response markers for IMPDH inhibition are conserved from in vitro cell lines to ex vivo treated primary samples from leukemia patients." (as PDF file) AACR Annual Meeting. Experimental and Molecular Therapeutics #3124. Washington, D.C., April 4, 2006.

J. Strovel, J. Jain, P. Natarajan, T. Lawrence, J. Castaneda, M. Chakiath, K. Zuck, M.W. Harding, K. Kelliher, B. Shames, R. Ramachandran, M.C. Botfield, D.K. Bol. "Global gene expression effects of AVN-944, a novel small molecule inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH)." (as PDF file) AACR Annual Meeting. Proc. Am. Assoc. Cancer Res. 47 (#3125) p.736, Washington, D.C., April 4, 2006.