Posted by rob on June 28, 2005 under Uncategorized | 
Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D
Nat Med. 2005 Jun 26;
The Poxviridae family members vaccinia and variola virus enter mammalian cells, replicate outside the nucleus and produce virions that travel to the cell surface along microtubules, fuse with the plasma membrane and egress from infected cells toward apposing cells on actin-filled membranous protrusions. We show that cell-associated enveloped virions (CEV) use Abl- and Src-family tyrosine kinases for actin motility, and that these kinases act in a redundant fashion, perhaps permitting motility in a greater range of cell types. Additionally, release of CEV from the cell requires Abl- but not Src-family tyrosine kinases, and is blocked by STI-571 (Gleevec), an Abl-family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Finally, we show that STI-571 reduces viral dissemination by five orders of magnitude and promotes survival in infected mice, suggesting possible use for this drug in treating smallpox or complications associated with vaccination. This therapeutic approach may prove generally efficacious in treating microbial infections that rely on host tyrosine kinases, and, because the drug targets host but not viral molecules, this strategy is much less likely to engender resistance compared to conventional antimicrobial therapies.
Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases.
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MELBOURNE, Australia, and MENLO PARK, Calif. and GENEVA, June 27 /PRNewswire-FirstCall/ — ChemGenex Pharmaceuticals Limited (ASX: CXS, Nasdaq: CXSP), based in Melbourne, Australia and Menlo Park, California, U.S.A., and Stragen Pharma S.A., based in Geneva, Switzerland, today announced an international alliance to accelerate the clinical development of ChemGenex’s lead anti-cancer therapeutic, Ceflatonin®.
Ceflatonin® is currently in a Phase 2 Clinical Trial at the M.D. Anderson Cancer Center in Houston, Texas treating chronic myeloid leukemia (CML) patients who are resistant to Gleevec®. In addition to CML, Ceflatonin® has established clinical activity in other hematological malignancies (blood cell cancers) including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
ChemGenex and Stragen will combine their respective strengths to pursue clinical approval of Ceflatonin® in the US, Europe, Australia and other territories. ChemGenex provides expertise in drug development and clinical trial management while Stragen offers GMP manufacturing, distribution, and marketing expertise.
Stragen has a patented manufacturing process for a semi-synthetic highly purified form of homoharringtonine, the active molecule in Ceflatonin® and has patented a suite of derivative molecules of homoharringtonine. ChemGenex will exclusively license the global rights to Stragen’s manufacturing process and novel analogues under the terms of the alliance.
Under the terms of the alliance ChemGenex will be responsible for the global clinical development of Ceflatonin®, as well as registration and marketing in North America and Asia-Pacific. Stragen will be responsible for drug production and global supply, as well as facilitating regulatory approvals within Europe. In addition, ChemGenex will engage Stragen’s established European clinical network to accelerate the development of Ceflatonin®. Once Ceflatonin® is approved in Europe, the alliance partners will market the product under the ChemGenex brand. The eventual profit split of sales in this territory will be shared ChemGenex 49%, Stragen 51%.
“The alliance with Stragen is a great opportunity for both companies to capitalize on our respective strengths and to accelerate the development of Ceflatonin® as a potential new therapy for chronic and acute leukemia,” said Greg Collier, Ph.D., chief executive officer and managing director of ChemGenex Pharmaceuticals. “This alliance expands ChemGenex’s global presence and gives us an outstanding partner with whom to progress regulatory approval and eventual marketing of Ceflatonin® in Europe.”
“We are very pleased to be able to partner with ChemGenex on the development of this promising anticancer drug,” said Jean-Luc Tetard, president of Stragen Pharma. “Stragen’s manufacturing capabilities and established European drug distribution and marketing network, combined with ChemGenex’s strong clinical development and pharmaceutical marketing capabilities make this an ideal partnership for the development and commercialization of Ceflatonin®.”
Benefits of the alliance
— Access to a European investigator network to accelerate clinical
development.
— A strong combined patent portfolio around homoharringtonine and
related analogs to provide broader and longer market exclusivity.
— Leverages each party’s respective strengths in clinical development,
marketing and manufacturing.
— Establishes a commercial infrastructure for ChemGenex in Europe.
About ChemGenex Pharmaceuticals Limited (http://www.chemgenex.com)
ChemGenex Pharmaceuticals is a gene-based pharmaceutical company dedicated to improving the lives of patients by developing therapeutics in the areas of oncology, diabetes, obesity, and depression. ChemGenex currently has two compounds in Phase 2 clinical trials, Ceflatonin® for leukemia and Quinamed® for solid tumors, and has a significant portfolio of anti-cancer, diabetes, obesity and depression programs. The company’s diabetes and obesity program is partnered with Merck KGaA and the depression program is partnered with Vernalis plc. ChemGenex currently trades on the Australian Stock Exchange under the symbol “CXS” and the NASDAQ exchange under the symbol “CXSP”.
Safe Harbor Statement
Certain statements made herein that use the words “estimate,” ‘project,” “intend,” “expect,” “believe,” and similar expressions are intended to identify forward-looking statements within the meaning of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements involve known and unknown risks and uncertainties which could cause the actual results, performance or achievements of the company to be materially different from those which may be expressed or implied by such statements, including, among others, risks or uncertainties associated with the development of the company’s technology, the ability to successfully market products in the clinical pipeline, the ability to advance promising therapeutics through clinical trials, the ability to establish our fully integrated technologies, the ability to enter into additional collaborations and strategic alliances and expand current collaborations and obtain milestone payments, the suitability of internally discovered genes for drug development , the ability of the company to meet its financial requirements, the ability of the company to protect its proprietary technology, potential limitations on the company’s technology, the market for the company’s products, government regulation in Australia and the United States, changes in tax and other laws, changes in competition and the loss of key personnel. These statements are based on our management’s current expectations and are subject to a number of uncertainties that could change the results described in the forward-looking statements. Investors should be aware that there are no assurances that results will not differ from those projected.
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Source: ChemGenex Pharmaceuticals Limited
ChemGenex and Stragen Pharma Create Alliance to Accelerate Clinical Development and Commercialization of Ceflatonin(R)
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Monday, June 27, 2005
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Cancer Drug Slows Poxvirus in Mice
Mice given a relatively new cancer drug can survive an otherwise lethal dose of vaccinia virus, a relative of smallpox virus, report scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The findings, say the investigators, suggest that Gleevec or similar drugs might be useful in preventing adverse side effects of smallpox vaccine. The classic smallpox vaccine is made from live, weakened vaccinia virus and is not recommended for people with compromised immunity, except in emergency situations where they may have been exposed to smallpox virus.
“This study helps illuminate the cellular machinery used by poxviruses to exit infected cells, and also provides new support for the concept of treating viral infections by targeting specific host cell molecules rather than the viruses themselves,” says NIAID Director Anthony S. Fauci, M.D.
The senior author of the paper, published online this week in the journal Nature Medicine, is Daniel Kalman, Ph.D., of Emory University School of Medicine in Atlanta.
Like all viruses, poxviruses co-opt various cellular molecules and processes to enter a cell, replicate and then spread to uninfected cells. Using lab-grown cells, Dr. Kalman and his colleagues identified specific cell proteins vaccinia uses to detach from an infected cell and move toward an uninfected cell. The proteins, members of the Abl-family (pronounced “able”) of tyrosine kinases, are well known to cancer investigators because mutation of one family member, Abl, causes a rare form of cancer known as chronic myelogenous leukemia (CML). Gleevec inhibits Abl-family tyrosine kinases and has proved very useful in treating CML.
To learn whether Gleevec could prevent or lessen vaccinia’s ability to spread in a living organism, the researchers treated mice with either saline solution or with Gleevec at a dose equivalent to that given to humans being treated for CML. Next, they exposed the mice to ordinarily lethal amounts of vaccinia. All of the Gleevec-treated mice survived, while 70 percent of the untreated mice died.
This finding, if confirmed in additional animal model studies, suggests that Gleevec might play a role in addressing a public health emergency in the event of a smallpox outbreak, Dr. Kalman says. Specifically, Gleevec might be useful as a preventive against adverse effects of smallpox vaccine, enabling clinicians to use the vaccine even in people who otherwise could not take it. Given for a short period, Gleevec theoretically could hamper the cell-to-cell spread of virus and allow the body’s immune system to mount a successful defense, he explains. Experiments to test whether Gleevec might work against smallpox virus as well as against vaccinia virus are now being planned, Dr. Kalman says. “The approach of fighting disease by targeting drugs to cellular molecules rather than to disease agents themselves may be applicable to a wide variety of pathogenic microorganisms,” he says.
Routine vaccinations for smallpox ended in this country in the early 1970s, and the World Health Organization declared smallpox eradicated in 1980. Nevertheless, concern remains that smallpox virus could be unleashed through an act of bioterror. For this reason, scientists are working to better understand the mechanisms of smallpox disease and to develop new and improved smallpox treatments and vaccines.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Reference: PM Reeves et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinasas. Nature Medicine DOI: 10.1038/nm1265 (2005).
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Cancer Drug Slows Poxvirus in Mice, June 27, 2005 Press Release – National Institutes of Health (NIH)
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A sunflower in a field near Serpa, Alentejo, 220 km east of Lisbon.
