Cytogenix working with Genta?
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http://www.bio-itworld.com/news/021804_report4453.html
Genasense Faces Identity Crisis
By Malorye A. Branca
Bio-IT World
BOSTON (02/18/04)—The first new drug in 20 years for advanced melanoma could make its way into doctors' hands this summer. Combined with chemotherapy, Genta's antisense drug Genasense (G3139) appreciably extends lives in patients with this almost untreatable cancer, and shows promise against other tumors as well.
The promise of Genasense enticed Aventis to enter a $480-million collaboration with Genta in 2002, and forecasters are bullish on its prospects. "With additional indications, it has blockbuster potential," says Tracy DeGregorio at Decision Resources.
But new evidence suggests this drug's success owes nothing to its intended mechanism — blunting the expression of a well-known cancer gene BCL2. Lingering confusion about Genasense's precise mechanism of action raises new questions about the antisense approach in general, and G3139 in particular.
Surprisingly, the man asking the questions actually helped develop Genasense. Cy Stein of the Albert Einstein College of Medicine is an antisense pioneer, sits on Genta's scientific board, and is due royalties once the drug hits the market. So why is he raising questions now? "My scientific credibility is at stake," he replies. "I've spent my career saying these compounds are more complicated than we thought."
Stein's findings will be published in an upcoming issue of Clinical Cancer Research. He uncovered this new evidence while testing RNAi in collaboration with Dharmacon — specifically, two siRNAs that suppress BCL2 protein and mRNA levels by 85 percent to 90 percent for up to eight days.
"The best [siRNA] was really spectacular," Stein says, "and the results were reproducible." But to his surprise, both the siRNA-treated and untreated tumor cells showed the same degree of changes after a dose of chemotherapy. It was only when G3139 alone was administered that more cells stopped growing. Nor did the group see any "synergistic effect" between G3139 and chemotherapy, suggesting Genasense works by itself, not in concert with other drugs.
In another study, Stein tested the effects of fragments of G3139, which proved as effective at stopping cancer growth as the full-length molecule (Lai, J.C. et al. Molecular Cancer Therapeutics 2, 1031-43; 2003).
Stein suspects Genasense works by inducing an immune response that weakens cancer cells. Although he admits his work needs validation — the RNAi studies were conducted in a prostate cancer cell line, which may not mimic actual patients — he maintains, "Every study I do points to the same thing."
Stop Making Sense
Genta's CEO, Raymond Warrell, disputes Stein's theory. "It's fine to have all kinds of hypotheses, but they need to be proven," he says edgily. "You can give interferon exogenously, and you will not see the kind of effects we see [with Genasense]."
Warrell's reaction isn't surprising. Initial results from the Phase III trial were less than clear-cut, but there were signs the drug works better than standard therapy, which helps a meager 7 percent of patients. Genta expects to learn this month if the drug will receive priority review by the FDA.
Warrell maintains that BCL2 downregulation is the only mechanism ever "proven" for this compound, making Genasense a bona fide antisense inhibitor. But, Stein notes, "It's clearly established that if you upregulate BCL2, you get cells that are resistant to chemotherapy; nobody has proven that downregulating BCL2 makes cells less resistant."
Harvard University's Stanley Korsmeyer, who cloned the BCL2 gene, agrees with Stein: "It is an open question ... whether once a cancer is established, BCL2 is required for its maintenance."
Regardless of mechanism, both Stein and Warrell expect the drug to succeed. Genasense "has doubled response rates, providing a 60-percent improvement in progression-free survival," Warrell says. "It improved overall survival by about 25 percent in patients who were refractory to other treatment."
Some analysts are unconvinced. "We have to wait and see," says Quyn Pham at Delafield Hambrecht. Needham & Co.'s Mark Monane, however, thinks Aventis and Genta have already "put together a compelling argument." He too is wary about the drug's mechanism of action but believes Genasense holds promise against other cancers, particularly given the dismal record of prior therapies.
Genasense would become only the second antisense molecule to win FDA approval, following Isis Pharmaceuticals' Vitravene, for cytomegalovirus retinitis. That would be a huge victory for the technology that has seen its share of disappointments. "The field is labeled as a sector," says Patrick Iversen, AVI BioPharma's senior vice president of research and development. "Good news, like bad news, can affect us all."
However, AVI and Isis say they do not see such off-target effects because they are working on "second generation" compounds, fundamentally different from Genasense. "We don't have those effects, and so we can predict the next success," Iversen says.
Antisense therapy has been poised for a breakthrough for several years. Establishing the mechanism of Genasense is clearly important to the scientists. But investors may not be as worried. As Monane says, "If it works, it works."
Antisense on Trial
Company Compound/Indications Phase
Antisense Pharma
AP-12009/Cancer Phase IIb
AVI BioPharma
Resten-NG/Restenosis Phase III
(planned)
AVI-4020/West Nile virus Phase II
AVI-4557/Drug metabolism Phase II
AVI-4126/Polycystic kidney disease Phase II
Oncomyc-NG/Cancer Phase I
Genta
Genasense/Melanoma, other cancers Phase III
Hybridon
GEM231/Various cancers Phase I
GEM-92/HIV Phase I
HYB-2055/Cancer Phase I
Isis Pharmaceuticals
Affinitak/Lung and other cancers Phase III
Alicaforsen/Crohn's disease Phase III
Alicaforsen/Ulcerative colitis Phase II
ISIS-14803/Hepatitis C Phase II
ISIS-1048030/Rheumatoid arthritis Phase II
ISIS-1048030/Psoriasis Phase II
ISIS-113715/Diabetes Phase II
ISIS-112989/ Phase I
Lorus Therapeutics
GTI-2040/Cancer, including breast, kidney, and myeloid leukemia Phase II
GTI-2501/Cancer Phase I
MethylGene
MG-98/ Phase I
NeoPharm
LErafAON/Cancer, including pancreatic Phase I/II
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Now look at the October PR from CYGX re: Cy Stein and melanoma...
CytoGenix Announces a Research Collaboration Agreement with Albert Einstein College of Medicine for Pre-Clinical Testing of a Gene Silencing Agent for Melanoma Cells
Houston, TX, (October 30, 2003) Cytogenix, Inc. (OTCBB: CYGX)
CytoGenix (CYGX:OTCBB) announced Thursday that it has entered into an agreement with the Albert Einstein College of Medicine, Department of Oncology for studies using the Company's proprietary gene silencing DNA technology against a gene that is expressed in melanoma cells that produces a protein known to counteract the effect of several chemotherapeutic agents in difficult to treat cancers.
These studies will be conducted in the laboratory of Dr. Cy Stein, professor of medicine, urology and molecular pharmacology. Dr. Stein is an outside Director of the Company and a member of its Scientific Advisory Board. Dr. Lyuba Berimetskaya, assistant professor of medicine will lead the investigation.
"As an Oncologist, I am keenly aware of the need for effective cancer therapies. This is why for the past fifteen years we have concentrated our research efforts on gene therapy." stated Dr. Stein. "We believe that the CytoGenix ssDNA technology has significant scientific merit and should be extensively tested for its potential use in the clinic as an effective cancer therapeutic agent." adds Dr. Stein.
"Our Company is heavily science driven and relations with scientists like Cy Stein and his colleagues tend to keep us focused on the important scientific issues related to successful product development." states Dr. Malcolm Skolnick, CytoGenix chairman and CEO.
CytoGenix, Inc. is a biopharmaceutical company that develops and markets innovative products and services based on its proprietary DNA expression technology. CytoGenix has products in pre-clinical development including, anti-herpes, anti-psoriasis and anti-inflammatory topical creams. The company owns a US patent for its core DNA expression technology and has 40 international or US pending patent applications.
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Perhaps Genasense produced intracellularly using Cytogenix's "proprietary gene silencing DNA technology"? Or am I completely misguided? ?????