Cancer :: AVN944 inhibits IMPDH & induces apoptosis-related biomarkers in patients with hematologic cancers

IMPDH is highly upregulated in most hematological cancers and solid tumors — an essential role in cancer cell synthesis of DNA and RNA. Inhibition of IMPDH represents a new and important approach to treat cancer. In a Phase I trial of AVN944, AvalonRx identified a set of 34 genes. These gene markers correlate with the biochemical effects of AVN944 on protein function — believed to result in tumor cell apoptosis at the right doses.

Avalon Pharmaceuticals, Inc. (NASDAQ and NYSE Arca: AVRX), presented a poster detailing the effect of AVN944 on a comprehensive set of genetic and biochemical biomarkers at the American Society of Hematology 48th Annual Meeting.

AVN944 demonstrated a statistically meaningful impact on IMPDH and other proteins that are critical to activities in cancer cells, including nucleotide biosynthesis, energy and metabolism, DNA replication, apoptosis and cell cycle control.

The data were collected in an ongoing Phase I open-label, repeat dose-escalation study designed to evaluate the safety and tolerability of AVN944 in patients with advanced hematologic malignancies and to determine the optimal dose for Phase II efficacy trials. Further data from an interim analysis of the trial is expected to be available shortly.

“IMPDH is highly upregulated in most hematological cancers and in many solid tumors,” said Beverly S. Mitchell, M.D., Deputy Director of the Stanford Comprehensive Cancer Center and George E. Becker Professor of Medicine at Stanford University. “IMPDH plays an essential role in cancer cell synthesis of DNA and RNA, and the inhibition of IMPDH represents a new and potentially important approach to the treatment of cancer.”

Analysis of the selected markers in patient samples from the Phase I trial showed a correlation of changes in the expression of these genes to dose level and duration of exposure. Importantly, several of these markers have been shown to reflect a durable, sustained stress response indicative of cancer cell death, particularly in cancer cells from AML patients. Specifically, it was found that the gene HspA1A, a marker of stress response found to correlate with depleted GTP pools in cancer cell lines, is induced within hours upon the first treatment of the drug in patients, even at the trial’s lowest doses. Following continued dosing of AVN944, this marker of disease cell stress was elevated even in the absence of circulating levels of the drug between doses. Other genes directly related to IMPDH inhibition showed similar response characteristics.

“AvalonRx?, our proprietary gene expression platform, enabled us to identify a set of 34 genes that reflect the mechanism-based activity of AVN944,” said David Bol, Ph.D., Senior Vice President of Product and Pharmaceutical Development at Avalon. “These gene markers correlate with the biochemical effects of AVN944 on protein function, which we believe will result in tumor cell apoptosis at the right doses. Our goal for the current Phase I study is to achieve those dose levels in patients. It is very encouraging that we have not seen any drug related adverse events even though we are already seeing biomarker movements consistent with significant inhibition of the IMPDH enzyme. This indicates the potential for a good therapeutic window. Additionally, these data showcase the power of the AvalonRx? technology in understanding the pharmacologic, pharmacodynamic and biologic activity of a drug on patients in early clinical studies.”

This analysis of the trial data was intended to describe how these biomarkers correlate with biologic activity of the drug in patients as the doses escalate. When comparing patients with different hematologic cancers, examination of the complete set of markers clearly demonstrated the utility of comprehensive gene expression analysis in clinical trials by distinguishing individuals with similar diseases, as well as patients with different malignancies, based on the makeup of their disease prior to drug administration as well as the different nature of the cellular response following drug administration.

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