Avalon's AVN944 Inhibits IMPDH and Induces Apoptosis-Related Biomarkers in Patients With Hematological Cancers
December 11 2006 - 6:30AM
PR Newswire (US)
- Data Presented at the American Society of Hematology 2006 Annual
Meeting - GERMANTOWN, Md., Dec. 11 /PRNewswire-FirstCall/ -- 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(R), 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(R)
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. An abstract of the Presentation, entitled,
"Genetic and Biochemical Biomarkers of IMPDH Inhibition in Phase I
Dose Escalation of AVN944 for Hematological Malignancies," is now
available on the ASH website, http://www.hematology.org/.
Conference Call and Webcast The Company will host a conference call
on Thursday, December 14, 2006 at 8 a.m. Eastern Time to provide a
full update on the interim results of the AVN944 Phase I trial.
Interested investors, analysts, members of the media and the
general public can listen to the call live over the Internet from
the investor section of the Company's Web site or by dialing the
numbers listed below. Conference Call Details:
------------------------ Dial-In: (866) 202-4367 (617) 213-8845
(International) Passcode: 78269925 Webcast: Please go to
http://www.avalonrx.com/, Investors, within 15 minutes prior to the
call and select the webcast link. The conference call replay will
be available through June 1, 2007 on Avalon's website
(http://www.avalonrx.com/). About AVN944 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. About AvalonRx(R) AvalonRx(R) is a comprehensive,
innovative and proprietary suite of technologies based upon
large-scale gene expression analysis. This platform facilitates
drug discovery by expanding the range of therapeutic targets for
drug intervention, including targets and target pathways frequently
considered intractable using conventional HTS approaches, allows
more informed decisions about which compounds to advance towards
clinical trials and facilitates drug development through
identification of biomarkers of efficacy that can stratify patients
or provide early indicators of response. About Avalon
Pharmaceuticals Avalon Pharmaceuticals is a biopharmaceutical
company using its proprietary technology, AvalonRx(R), to discover
and develop cancer therapeutics. Avalon has a lead product in Phase
I clinical development (AVN944 - IMPDH inhibitor), preclinical
programs to discover inhibitors for the Beta-catenin, Aurora and
Survivin pathways and drug discovery collaborations with MedImmune,
Novartis, ChemDiv and Medarex. Avalon Pharmaceuticals was
established in 1999 and is headquartered in Germantown, Md. Safe
Harbor Statement This announcement contains, in addition to
historical information, certain forward-looking statements that
involve risks and uncertainties, in particular, related to clinical
progress in the development of AVN944. Such statements reflect the
current views of Avalon management and are based on certain
assumptions. Actual results could differ materially from those
currently anticipated as a result of a number of factors, risks and
uncertainties including the risk that AVN944 will not progress
successfully in its clinical trials, and other risks described in
our SEC filings. There can be no assurance that our development
efforts will succeed, that AVN944 will receive required regulatory
clearance or, even if such regulatory clearance is received, that
any subsequent products will ultimately achieve commercial success.
The information in this Release should be read in conjunction with
the Risk Factors set forth in our 2005 Annual Report on Form 10-K
and updates contained in subsequent filings we make with the SEC.
Contacts: Avalon Pharmaceuticals, Inc. Noonan Russo Gary Lessing
Wendy Lau (Media) Executive Vice President & CFO Tel: (212)
845-4272 Tel: (301) 556-9900 Fax: (301) 556-9910 The Trout Group
LLC Email: Chad Rubin (Investors) Tel: (212) 477-9007 ext. 47
DATASOURCE: Avalon Pharmaceuticals, Inc. CONTACT: Gary Lessing,
Executive Vice President & CFO of Avalon Pharmaceuticals, Inc.,
+1-301-556-9900, Fax: +1-301-556-9910, ; or Media: Wendy Lau of
Noonan Russo, +1-212-845-4272; or Investors: Chad Rubin of The
Trout Group LLC, +1-212-477-9007 ext. 47, both for Avalon
Pharmaceuticals, Inc. Web site: http://www.avalonrx.com/
http://www.hematology.org/
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