Avalon Pharmaceuticals has announced the results of an AVN944 biomarker study that utilized Avalon's proprietary AvalonRx technology to identify gene signatures that may be useful for patient stratification.
The poster presentation entitled "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," was given at the American Association for Cancer Research Annual Meeting held April 14-18, 2007, in Los Angeles. The study described the generation of biomarkers that may have utility in identifying patients most likely to benefit from AVN944 therapy.
"Our biomarker-driven approach to drug development allows us the opportunity to enrich our clinical trials with patient populations more sensitive to AVN944 therapy," stated Jeffrey Strovel, Ph.D., senior scientist at Avalon and lead investigator in the study. "We can now validate these gene signatures for utility in patient stratification in our upcoming Phase II trials, as well as for their use as prognostic signatures. If this approach works, it could significantly accelerate the development of AVN944 and enhance its utility as a marketed product."
AVN944 is an orally bioavailable inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH). IMPDH2 is highly up-regulated and required for the production of guanine nucleotides in many malignancies, including hematologic cancers. AVN944 has been in a repeat-dose, dose escalation trial in patients with advanced hematologic cancers including AML, CLL, Multiple Myeloma and lymphomas. To identify modes of sensitivity and resistance to AVN944 therapy, Avalon developed a resistant Multiple Myeloma cell line, RPMI- 8226R. RPMI-8226R was subjected to microarray gene expression profiling, and guanosine triphosphate (GTP) level was determined with the objective of comparing these biomarkers to the same markers in patient samples from the Phase I clinical trial. Upon comparison of gene expression signatures from patients enrolled in the AVN944 clinical trial to RPMI-8226R, a gene signature was identified that distinguished patients receiving multiple rounds of therapy from those that derived no benefit from AVN944.
These gene expression signatures will be evaluated further in a Phase II trial to examine their utility in the enrichment of patients likely to benefit from AVN944 therapy. Currently, Avalon researchers are developing additional AVN944 resistant cell lines derived from solid tumor cells to develop a better understanding of the molecular modes of sensitivity and resistance in preparation for upcoming clinical trials in solid tumors.
AVN944 is an oral small molecule drug candidate that inhibits inosine monosphospate dehydrogenase (IMPDH), an enzyme that is critical for cells to be able to synthesize guanosine triphosphate (GTP), a molecule required for DNA synthesis and cellular signaling. IMPDH is over expressed in some cancer cells, especially in the case of hematological malignancies. In laboratory experiments, AVN944 has been shown to inhibit IMPDH activity in cells, and suppress pools of GTP. Anticancer activities of IMPDH inhibitors correlate with sustained depletion of GTP pools both in cellular models and in human subjects. AVN944 appears to have a selective effect on cancer cells in that deprivation of GTP in normal cells results in a temporary slowing of cell growth, while GTP deprivation in cancer cells induces cell death, or apoptosis.
Results from preclinical studies of AVN944 indicate that AVN944 inhibited the proliferation of lymphoid and myeloid cells, the principal cells involved in the most common types of human leukemias. In a single-dose, dose- escalation Phase I clinical trial of AVN944 conducted in the United Kingdom in healthy volunteers, AVN944: (1) was well tolerated at all tested doses with no notable side effects; (2) demonstrated good pharmacokinetic properties; and (3) had a significant inhibitory effect on IMPDH enzyme activity. Avalon filed an IND with the FDA in August 2005 and initiated U.S. Phase I clinical trials in January 2006 for the treatment of hematological cancers.