MethylGene Inc.: Further Preclinical Evidence of Synergy and Molecular Activity of MG98, A Novel Anticancer Compound, Disclosed at 2004 AACR
MONTREAL--(BUSINESS WIRE)--March 29, 2004--Two poster presentations - one demonstrating synergistic usage of MG98 in combination with interferon in renal cancer cells and another disclosing anticancer activity of MG98 as a single agent in gastric cancer cells - were presented at the 2004 AACR 95th Annual Meeting in Orlando, Florida, March 27-31, 2004.
Abstract #1602, which describes MG98 activity against gastric cancer, was presented by MethylGene Inc., a private biopharmaceutical company focused on developing new drugs for cancer and infectious diseases. Abstract #1609, which describes the activity of MG98 in combination with interferon against renal cancer cells was presented by investigators from The Cleveland Clinic. These preclinical results together with prior evidence of clinical activity of MG98 in patients with metastatic renal cell cancer, form the basis for MethylGene's planned randomized Phase I/II trial of MG98 in combination with interferon as first-line therapy in metastatic renal cancer. This is the first combination therapy trial run by MethylGene with MG98.
In a poster titled: "Antitumor activity of MG98, an antisense oligodeoxynucleotide targeting DNA methyltransferase-1 (DNMT1) in gastric carcinoma," MethylGene investigators demonstrated that specific inhibition of DNMT1 by MG98 resulted in significant cancer growth inhibition in a variety of human gastric cancer cell lines. Associated with growth impairment was concomitant re-expression of multiple methylation-silenced tumor suppressor genes including p16ink4a and RUNX3. In addition, MG98 inhibited growth of malignant tissue in mice previously implanted with human gastric cancer tumors. These data provide evidence that methylation-silenced tumor suppressor genes may play a key role in gastric tumor growth and that MG98 may have utility in the treatment of human gastric cancer.
The second poster presented by investigators from The Cleveland Clinic is titled: "Genes involved in sensitization of renal cancer cells to interferon-induced apoptosis after selective depletion of DNA methyltransferase-1 by antisense oligonucleotide (MG98)." The Cleveland Clinic, in collaboration with MethylGene, reports that in interferon-resistant renal cancer cells, MG98 treatment reactivated a methylation-silenced tumor suppressor gene called RASSF1A and sensitized the cancer cells to apoptosis in response to subsequent interferon challenge. Human genome array analyses also demonstrated that three genes that were upregulated in the renal cancer cells by MG98 treatment are implicated in apoptosis. This suggests a mechanistic basis for the observed increase in interferon-induced apoptotic cell death following MG98 treatment.
"These new data in gastric and renal cell carcinoma reinforce the important role of hypermethylation of tumor suppressor genes (gene silencing) in cancer and the potential clinical utility of MG98 as a valuable and effective anticancer compound," commented Dr. Jeffrey Besterman, Senior Vice President of Research and Development at MethylGene. "The results from our collaboration with The Cleveland Clinic demonstrate that silencing of genes by hypermethylation may contribute to interferon resistance of renal cancer cells and that pretreatment with MG98 may reverse interferon resistance in cancer cells."
MethylGene, with its corporate partner MGI PHARMA, has evaluated MG98 monotherapy in both solid and hematological malignancies. MG98 is a second-generation antisense oligonucleotide that inhibits the synthesis of DNA methyltransferase 1. In a related program, the Company has identified isotype-selective small molecule inhibitors of DNA methyltransferases that are being evaluated in preclinical models. The strategy to use a combination of MG98 and small molecule DNA methyltransferase inhibitors is well protected intellectual property. In that context, the Company is pleased that it recently received a patent from the Australian Patent Office titled: "Modulation of gene expression by combination therapy" (patent #766084).
About MethylGene
MethylGene is a biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for the global pharmaceutical market. The company's initial therapeutic focus is in cancer and infectious diseases. MG98, the most advanced anticancer product candidate, is in multiple clinical trials and partnered with MGI PHARMA for North American rights. The second oncology product candidate, MGCD0103, is a rationally designed, isotype selective, orally active small molecule HDAC inhibitor. Clinical trials in the U.S. and Canada are expected to commence during Q2 2004. MGCD0103 and nextgeneration candidates are licensed to Taiho Pharmaceutical Co. Ltd., a leading Japanese oncology pharmaceutical company, for Japan, Korea, Taiwan and China in a deal worth up to US$37.5 million. In addition, MethylGene has a preclinical small molecule inhibitor program against bacterial beta-lactamases which is partnered with Merck for worldwide rights in a deal worth US$33.75 million. In addition, MethylGene has a portfolio of other chemistry-driven research programs including HDAC inhibitors for non-oncology large market indications and two small molecule kinase programs for oncology. For more information about MethylGene, please visit www.methylgene.com.
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However, as seen from MOGN's horizon the MG98 program is kept on the backburner. From the recent 10K:
MG98 and Small Molecule DNA Methyltransferase Inhibitor Programs
In August 2000, as part of our strategy to expand our portfolio of marketed and development stage anti-cancer products, we entered into an exclusive license, research and development agreement with MethylGene Inc. for North America rights to its proprietary anti-cancer product candidate MG98 and its DNA methyltransferase small molecule inhibitor program. Included within our license rights is a United States patent on a method for reversing the tumor-causing state of a cell by administering an agent that corrects an aberrant methylation pattern in the DNA of the cell. MethylGene is a chemistry-driven, rational drug design and development company focused on the inhibition of enzyme targets that are associated with disease. It pursues two approaches to enzyme inhibition: rationally designed mRNA inhibitors that block the production of enzymes and rationally designed small molecule inhibitors that block the activity of enzymes.
In a December 2003 amendment to the License Agreement, MethylGene acknowledged full satisfaction of our payment obligations and suspended further payment obligations by us pending a planned June 2004 data review of the small molecule inhibitor program and following completion by MethylGene of a planned clinical trial with MG98. If we resume development, our financial responsibilities under the License Agreement would also resume.
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