Kerentech

Professor Andrew Loudon from the University of Manchester

Researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC) have successfully used a drug to reset and restart the natural 24 hour body clock of mice in the lab.

The ability to do this in a mammal opens up the possibility of dealing with a range of human difficulties including some psychiatric disorders, jet lag and the health impacts of shift work, like obesity.

Research was led by Professor Andrew Loudon from the University of Manchester and Dr Mick Hastings of the MRC Laboratory of Molecular Biology in Cambridge, working with a multi-disciplinary team of scientists from Pfizer led by Dr Travis Wager, and was published in PNAS.

Professor Loudon said “It can be really devastating to our brains and bodies when something happens to disrupt the natural rhythm of our body clocks. This can be as a result of disease or as a consequence of jet lag or frequent changing between day and night shifts at work.

Professor Janet Allen, BBSRC Director of Research

Most living creatures and plants have an internal body timing system – called the circadian clock. This is a complex system of molecules in every cell that drives the rhythmicity of everything from sleep in mammals to flowering in plants.

Light and the day and night cycle are very important for resetting the clock and the fine adjustments are made through the action of several enzymes, including one called casein kinase 1, which has been the centre of this research

Professor Loudon continued “The circadian clock is linked to the 24 hour day-night cycle and the major part of the clock mechanism ‘ticks’ once per day. If you imagine each ‘tick’ as represented by the rise and fall of a wave over a 24 hour period, as you go up there is an increase in the amount of proteins in the cell that are part of the clock mechanism, and as you go down, these substances are degraded and reduce again. What casein kinase 1 does is to facilitate the degradation part.

“So you can imagine that the faster casein kinase 1 works, the steeper the downward part of the wave and the faster the clock ticks – any change in casein kinase 1 activity, faster or slower, would adjust the ‘ticking’ from 24 hours to some other time period. Consider that if your body suddenly starts working on a 23 hour or 25 hour clock, many of your natural processes, such as sleeping and waking could soon become out of step with day and night.”

Dr Michel Goedert, Head of the Neurobiology Division at Medical Research Council Laboratory of Molecular Biology

The team found a drug that slows casein kinase 1 down and used it in mice where the circadian rhythm has ceased i.e. the clock has stopped ticking all together. In live mice and also in cells and tissue samples from mice, they were able to re-establish the ticking of the clock by using the drug to inhibit the activity of casein kinase 1.

Professor Loudon concluded “We’ve shown that it’s possible to use drugs to synchronise the body clock of a mouse and so it may also be possible to use similar drugs to treat a whole range of health problems associated with disruptions of circadian rhythms. This might include some psychiatric diseases and certain circadian sleep disorders. It could also help people cope with jet lag and the impact of shift work.”

Professor Janet Allen, BBSRC Director of Research said “The most effective way to develop drugs to treat a health problem is to understand the basic biology that underpins what is going on in our bodies. In this case, by understanding the basic biology of the enzyme controlling biological clocks the research team have been able to identify potential drug-based solutions to a range of issues that affect many people’s health and quality of life.”

Dr Michel Goedert, Head of the Neurobiology Division at Medical Research Council Laboratory of Molecular Biology said “We’re all familiar with jet-lag and that sense of being disoriented in time. What is probably less widely understood is how this effect can impact on those with certain mental illnesses. It is crucial to find out what can go wrong at the molecular and cellular level in the brain if we are to determine what treatments will work for patients. If further studies in humans confirm what this study has shown in mice, this could eventually lead to an entirely new approach to treating mental illnesses such as bipolar disorder.”

Dr. Wager, Associate Research Fellow, Pfizer said “It is amazing what can be accomplished when first-rate academic groups and pharmaceutical discovery units team up. Leveraging each other’s talents we now have a deeper understanding of the role casein kinase plays within biological systems. Having the ability to entrain or re-entrain an arrhythmic system opens the door to new treatment option for circadian rhythm disorders. Targeting the inhibition of casein kinase with small molecules may lead to the discovery of novel drugs for the treatment of bipolar depression and other circadian rhythm disorders. The burden of these disorders is enormous and new treatment options are needed.”

Kamada will receive $20 million upfront for the exclusive commercial rights to its emphysema treatment.

Kamada Ltd. today announced a definitive agreement with Baxter International Inc. ,  which will have exclusive commercial rights to Glassia (Alpha 1-Proteinase Inhibitor in the US, Australia, New Zealand and Canada.

Emphysema Image

Glassia, which was approved by the FDA on July 1, 2010, is provides chronic augmentation and maintenance therapy in individuals with emphysema due to congenital deficiency of alpha1-proteinase inhibitor, also known as alpha1-antitrypsin (AAT) deficiency. AAT deficiency is an under-diagnosed hereditary condition that may result in early onset emphysema. Baxter expects to introduce Glassia in the US during the fourth quarter of 2010, and will pursue distribution licenses for Glassia in the other countries for which it has obtained rights.

Baxter BioScience Global BioPharmaceuticals president Larry Guiheen said, “The agreement with Kamada underscores Baxter’s commitment to expanding the diagnosis of alpha1-antitrypsin deficiency by bringing new and innovative therapeutic options to Alpha-1 patients and their treating physicians.”

The distribution agreement includes an upfront cash payment by Baxter of $20 million. The agreement also includes a provision under which Kamada has agreed, for a limited period of time, not to initiate or enter any discussions or agreements relating to the commercialization of Glassia in certain other countries and for Kamada’s investigational next-generation inhaled therapy.

Under a separate license agreement, Baxter has been granted the right to process Glassia and will seek necessary regulatory approvals to enable it to do so. Under this agreement, Baxter may make additional payments of up to $25 million related to milestone achievements and the implementation of technology transfer related to the production of the therapy by Baxter, as well as royalties on product sales.

$ 1.1 B Agreement  beetwen Roche and Aileron

Aileron Therapeutics and Roche  announced today that they have entered into a collaboration to discover, develop and commercialise a new class of drugs called Stapled Peptide Therapeutics. As part of this agreement, Roche will work with Aileron to develop drug candidates against up to five undisclosed targets selected from Roche’s key therapeutic areas, which include oncology, virology, inflammation, metabolism and CNS.

Stapled Peptide Therapeutics are a result of Aileron’s breakthrough peptide stabilization technology, and are a potential solution to drug as-yet intractable disease targets, including those originating from long sought-after intracellular protein-protein interactions.

Under the terms of the agreement, Roche will provide Aileron guaranteed funding of at least $25 million in technology access fees and R&D support. Aileron is eligible to receive up to $1.1 billion in payments upon the achievement of discovery, development, regulatory and commercialisation milestones, if drug candidates are developed against all five targets. In addition, Aileron will receive royalties on future sales for any marketed products that result from the collaboration. Aileron will have substantial responsibility in collaboration with Roche to develop drug candidates against the selected targets up to clinical development.

“Roche is dedicated to advancing innovative therapies, and Stapled Peptides represent a potentially transformative new technology to create drugs for important disease targets that are intractable to currently available modalities,” said Jean-Jacques Garaud, Global Head of Roche Pharma Research and Early Development. “This collaboration with Aileron is a strategically important endeavour for advancing a novel approach to developing new medicines and will accelerate our progress toward our ultimate goal of bringing important new treatments to patients with unmet medical needs.”

“This alliance with Roche validates the broad potential for our Stapled Peptide platform across multiple therapeutic areas and classes of targets and also provides Aileron with capital to advance our platform and internal drug development pipeline,” said Joseph A. Yanchik, III, President and CEO of Aileron. “We took our time to carefully consider several opportunities for our first industry collaboration, and believe that Roche is an ideal partner for Aileron because of its history with peptide therapeutics and its commitment to tackling difficult disease targets.”

About Stapled Peptides

Aileron’s proprietary Stapled Peptide technology platform “locks” peptides into their biologically active shape, mimicking the structures found in nature. This process captures the best features of both small molecules and therapeutic proteins, ultimately endowing the peptide with unique and beneficial drug-like properties, including efficient cell penetration, improved pharmacokinetics, high-affinity binding to large target protein surfaces and excellent stability within the body. This unique combination of features could greatly expand the number of “druggable” therapeutic targets, by providing a unique opportunity to address the thousands of intracellular protein-protein interactions that remain a challenge for functional modulation by current therapeutics. In preclinical studies, Aileron’s Stapled Peptide Therapeutics have been shown to possess remarkable potency, in vivo stability and cell permeability.

About Aileron

Headquartered in Cambridge, Massachusetts, Aileron Therapeutics is a biopharmaceutical company leading the development of a new class of drugs called Stapled Peptide Therapeutics. Stapled Peptides are a breakthrough solution to address thousands of therapeutically important yet currently undruggable targets. Stapled Peptides have demonstrated their unique ability to penetrate cells throughout the body and modulate protein-protein interactions, critical control points for most human diseases. Founded in 2005 and supported by funding from a leading syndicate of investors, Aileron is building a robust pipeline of therapeutics for the treatment of cancer, infectious disease, metabolic disease and immune/inflammatory diseases. For more information: www.aileronrx.com.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2009, Roche had over 80,000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information:

AVI BioPharma Discloses New Contract With U.S. Government for Potential Funding of up to $291 Million to Advance Development of Therapeutic Candidates for Ebola and Marburg Hemorrhagic Fever Viruses

AVI BioPharma, a developer of RNA-based therapeutics, yesterday filed a current report on Form 8-K with the U.S. Securities and Exchange Commission providing the following disclosure:

On July 14, 2010, AVI BioPharma, Inc. was awarded a new contract with the U.S. Department of Defense Chemical and Biological Defense Program through the U.S. Army Space and Missile Defense Command for the advanced development of the Company’s hemorrhagic fever virus therapeutic candidates, AVI-6002 and AVI-6003, for Ebola and Marburg viruses, respectively. The contract is funded as part of the Transformational Medical Technologies (TMT) program, which was pioneered to develop innovative platform-based solutions countering biological threats.

The contract is structured into four segments with potential funding of up to approximately $291 million. Activity under the first segment is to begin immediately and provides for funding to the Company of up to approximately $80 million. After completion of the first segment, and each successive segment, TMT has the option to proceed to the next segment for either or both AVI-6002 and AVI-6003. If TMT exercises its options for all four segments, contract activities would include all clinical and licensure activities necessary to obtain FDA regulatory approval of each therapeutic candidate and would provide for a total funding award to the Company of up to approximately $291 million.

The contract was granted in response to proposals the Company submitted to a Request for Proposal (RFP) issued in November 2009 and initially submitted by the Company in February 2010. Under an earlier contract the Company completed development activities that culminated in the opening of Investigational New Drug (IND) applications for both AVI-6002 and AVI-6003.

AVI-6002 and AVI-6003 are RNA-based therapeutic candidates from the Company’s anti-infective portfolio and use AVI’s proprietary PMOplus(TM) chemistry.

About the Transformational Medical Technologies (TMT) Program

The TMT program was created by the DoD to protect the Warfighter from emerging and genetically altered biological threats by discovering and developing a wide range of medical countermeasures through enhanced medical research, development, test and evaluation programs. The TMT Program Office is matrixed from the Joint Science and Technology Office — DTRA and Joint Program Executive Office — Chemical and Biological Defense, with oversight from the Office of the Secretary of Defense. For more information on TMT, visit http://www.tmti-cbdefense.org.

About AVI BioPharma

AVI BioPharma is focused on the discovery and development of novel RNA-based therapeutics for rare and infectious diseases, as well as other select disease targets. Applying pioneering technologies developed and optimized by AVI, we are able to target a broad range of diseases and disorders through distinct RNA-based mechanisms of action. Unlike other RNA-based approaches, our technologies can be used to directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate (inhibit) or up-regulate (promote) the expression of targeted genes or proteins. By leveraging our highly differentiated RNA antisense-based technology platform, we have built a pipeline of potentially transformative therapeutic agents, including a clinical stage Duchenne muscular dystrophy candidate and anti-infective candidates for influenza and hemorrhagic fever viruses.

A study found that Alzheimer’s disease patients that used the new long-acting version of Aricept were more likely to maintain or improve brain function than those who continued using  the older formulation.

Improvement benefited the most to people with more advanced Alzheimer’s. Comparison between the experimental  23-milligram tablet taken once daily with the immediate-release, 10-milligram pill now used,  was favorable to the new formulation,  according to the results released today at the International Conference on Alzheimer’s Disease in Honolulu. No new side effects were seen, the study said.

Tokyo-based Eisai is counting on long-acting and patch versions of Aricept, the world’s best-selling drug for Alzheimer’s, to buffer a potential sales decline when the medicine loses patent protection in the U.S. in November. The company, which generates 60 percent of Aricept’s global sales in the U.S., expects the drug’s revenue in that market to fall about 50 percent in the year ending March 2012, it said in March.

The new formulation is being reviewed by the U.S. Food and Drug Administration, which will make a decision by July 24. It plans to submit data this quarter for regulatory approval to sell the patch version. Eisai aims for the long-acting version of Aricept to reach more than $600 million in peak sales.

The study involved 1,467 people who had moderate to severe Alzheimer’s disease and underwent treatment with the immediate- release Aricept pill for more than three months. Patients then took placebo and either the immediate-release or extended- release pill for six months.

Aricept sales for Eisai rose 6.3 percent to 322.8 billion yen ($3.64 billion) in the year ended March 31, accounting for 40 percent of revenue. The Japanese company pays New York-based Pfizer a fee for co-promotion of Aricept in the U.S. and parts of Europe.

Calithera Biosciences, a company developing novel oncology therapeutics, today announced the completion of a Series A financing totaling $40 million. The capital will be used to support the company’s pioneering efforts to develop activators of caspases, the proteases that promote apoptotic cell death, for the treatment of cancer and other proliferative diseases.

“Promoting apoptosis in cancer cells is a validated approach to the treatment of cancer, as many oncology drugs on the market today are known to kill tumor cells by activating apoptotic pathways, albeit through indirect means,” said Susan Molineaux, Ph.D., co-founder and Chief Executive Officer of Calithera.  “By targeting caspases directly, we hope to develop agents that have broad utility across many types of cancer, with greater specificity than current treatments and the potential to overcome chemoresistance.”

Calithera’s technology was developed by and licensed from the laboratory of co-founder James Wells, Ph.D., chair of the Department of Pharmaceutical Chemistry in the University of California, San Francisco School of Pharmacy.  Dr. Wells’s laboratory has successfully identified several novel compounds that selectively activate procaspases and trigger apoptosis in cancer cells.  Proceeds from the financing will be used to advance one or more caspase activators through preclinical development and into Phase 1 clinical trials in cancer patients.  In parallel, the company will expand its technology for targeting allosteric activating sites to other enzymes with therapeutic potential in cancer.

“Most drug discovery efforts are focused on identifying drugs that inhibit enzyme function,” said Dr. Wells.  “But, interestingly, many cellular enzymes remain dormant until activated.  In the case of caspases, they can be activated on demand by mimicking the natural process with small molecules.”

Expert Leadership Team in Place

The management team of Calithera brings to the company both deep scientific expertise and extensive experience in drug development.

Susan Molineaux, Ph.D., was most recently a founder and Chief Executive Officer of Proteolix, a company that developed proteasome inhibitors.  Proteolix was in late-stage clinical trials with carfilzomib in multiple myeloma when Onyx Pharmaceuticals acquired the company in 2009 for $851 million.  Prior to forming Proteolix, Dr. Molineaux held leadership positions at Rigel Pharmaceuticals and Praecis Pharmaceuticals.  Dr. Molineaux began her career as a scientist in the Immunology group at Merck.

Mark Bennett, Ph.D., Senior Vice President of Research at Calithera, was Vice President of Research at Proteolix.  Previously, he was Director of Cell Biology at Rigel Pharmaceuticals.  Prior to that, Dr. Bennett served as an Assistant Professor in the Department of Molecular and Cell Biology at University of California, Berkeley.

Eric Sjogren, Ph.D., Senior Vice President of Drug Discovery at Calithera, was most recently the Vice President and Head of Medicinal Chemistry at Roche, Palo Alto.  He held a series of positions during his 15-year tenure at Roche.  Prior to that, Dr. Sjogren was at Syntex for eight years.

About Caspases in Cancer

The direct activation and targeting of caspases represents a novel approach to inducing apoptosis in cancer cells and may have utility across a broad range of cancer types while avoiding chemoresistance.  Caspases are the proteases responsible for initiating apoptosis, or programmed cell death, in cancer cells.  Cancer cells grow in an uncontrolled manner in part through their ability to develop mechanisms to resist apoptosis.  Many classic cancer therapies (cytotoxic drugs and radiation therapy) work by inducing upstream pro-apoptotic pathways that then activate caspases to overcome this resistance.

About Calithera Biosciences

Calithera Biosciences was founded in 2010, with core technologies licensed from the University of California, San Francisco, to develop novel therapeutic approaches to the treatment of cancer.  The company is developing small molecules that directly activate caspases, the proteases responsible for initiating programmed cell death, or apoptosis, in cancer cells.  Calithera plans to develop activators of additional enzymes as therapeutic agents for the treatment of cancer and other proliferative diseases.  Located in South San Francisco, CA, Calithera Biosciences is privately held.

Infinity Pharmaceuticals, Inc. and Intellikine, Inc., a leader in the development of small molecule drugs targeting the PI3K/mTOR pathway, today announced an agreement under which Infinity obtained global development and commercialization rights to Intellikine’s portfolio of inhibitors of the delta and gamma isoforms of phosphoinositide-3-kinase (PI3K). Among these inhibitors is INK1197, an orally available dual delta/gamma-specific inhibitor of PI3K for which clinical development in inflammatory diseases is expected to commence in 2011.

Under the terms of the agreement, Intellikine will receive $13.5 million in initial license payments, committed research funding over the first two years of the relationship to identify additional novel delta, gamma and dual delta/gamma-specific inhibitors of PI3K for future development, up to $25 million in success-based milestones for the development of two distinct product candidates, and up to $450 million in success-based milestones for the approval and commercialization of two distinct products. In addition, Intellikine will be entitled to receive royalties upon successful commercialization of products licensed to Infinity. For products directed primarily to oncology indications, Intellikine will have the option, at the end of Phase 2 clinical development and upon payment of an option fee, to convert its royalty interest in U.S. sales into the right to share in 50% of profits and losses on U.S. development and commercialization, and to participate in up to 30% of the detailing effort for these products in the United States.

The PI3Kdelta/gamma program licensed from Intellikine will be a part of Infinity’s existing strategic alliance with Mundipharma International Corporation Ltd. and will be governed by the same terms as Infinity’s internally-discovered programs. Such terms include Mundipharma’s funding of Infinity’s research and development expenses for the PI3K program through the later to occur of December 31, 2013 and the commencement of Phase 3 development, subject to aggregate funding caps across the partnered portfolio under a three-year rolling plan, and reimbursement of 50% of research and development expenses thereafter. In addition, Mundipharma will have commercialization rights outside of the United States to any successfully developed products, subject to the payment of royalties of up to 20% on net sales.

“This agreement is emblematic of Infinity’s strategy to use our scientific expertise and financial strength to expand our portfolio of high-quality development programs in areas where there is a significant unmet medical need and for which Infinity is well positioned to reveal — and then realize — the potential of such programs. We expect to seek additional opportunities to broaden our portfolio of innovative product candidates in the future,” said Adelene Q. Perkins, president and chief executive officer of Infinity. “We are excited to develop INK1197 in inflammation and to work closely with the Intellikine team to identify additional differentiated PI3Kdelta/gamma inhibitors for both inflammation and oncology,” said Julian Adams, Ph.D., president of research and development at Infinity. “Targets such as PI3Kdelta and PI3Kgamma have broad applicability across inflammatory and oncology indications, creating many opportunities to make a meaningful impact for patients.”

“Intellikine has rapidly assembled a leading pipeline of drug candidates against the PI3K/mTOR pathway,” said Troy Wilson, Ph.D., J.D., president and chief executive officer of Intellikine. “We are excited to work with our colleagues at Infinity, who share our strong scientific culture and sense of urgency to advance this program forward. Additionally, this collaboration provides us with significant resources to advance our own TORC1/2 and PI3Kalpha drug candidates. The opportunity to co-develop and co-detail PI3Kdelta/gamma drug candidates in oncology with Infinity is a key component of our strategy to build an oncology business.”

By virtue of the expansion of Infinity’s portfolio to include the PI3Kdelta/gamma program, Infinity expects to exceed the $65 million cap for 2010 set forth in the research plan under the Mundipharma/Purdue Pharma alliance. As a result, Infinity now projects a 2010 cash burn of between $35 and $45 million and a year-end cash balance of between $85 and $95 million, not including amounts that may be drawn by Infinity under the $50 million line of credit available from Purdue. Infinity continues to expect that its current cash and investments, together with research and development funding from Mundipharma and Purdue and proceeds from the line of credit, are sufficient to fund the company’s operations into 2013 and enable the company to reach key development milestones and evaluate additional external opportunities to strategically enhance its pipeline.

About PI3K and INK1197

The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta and gamma isoforms of PI3K are strongly implicated in immune-mediated inflammatory and allergic disorders. Restricted primarily to cells of the immune system, these two isoforms regulate diverse cellular functions of the immune system. INK1197 is an orally-available, small molecule, dual-selective inhibitor of PI3Kdelta and PI3Kgamma. INK1197 has demonstrated activity in preclinical models of rheumatoid arthritis, allergy and inflammation. Infinity intends to develop INK1197 in immune-mediated inflammatory diseases. Beyond INK1197, Intellikine will contribute its collection of novel PI3Kdelta-selective and PI3Kdelta/gamma dual-selective compounds, providing multiple opportunities for Infinity to develop differentiated therapies against inflammatory and autoimmune diseases as well as hematologic cancers.

About Infinity Pharmaceuticals, Inc.

Infinity is an innovative drug discovery and development company seeking to discover, develop, and deliver to patients best-in-class medicines for difficult-to-treat diseases. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging disease pathways. Infinity’s programs in the inhibition of the Hsp90 chaperone system, the Hedgehog pathway and fatty acid amide hydrolase are evidence of its innovative approach to drug discovery and development.

About Intellikine, Inc.

Intellikine is a private, clinical-stage company focused on the discovery and development of innovative small molecule drugs targeting the PI3K/mTOR pathway. Intellikine’s most advanced program, INK128, a selective TORC1/2 inhibitor for the treatment of cancer, is currently in a Phase 1 clinical trial in patients with advanced solid tumors. In addition, Intellikine was recently awarded a $1 million grant from the Multiple Myeloma Research Foundation to advance INK128 as a potential treatment for patients with multiple myeloma. Intellikine is also advancing a first-in-class PI3Kalpha-selective inhibitor, INK1117, which is currently being prepared for human clinical trials in cancer. Beyond INK128 and INK1117, Intellikine has generated one of the leading pipelines of drug candidates against important therapeutic targets in this pathway.

By Sarkis Mazmanian as told to Sara McBride:: The Scientist ::Volume 23 | Issue 8 | Page 34

Just one molecule can make the difference in mediating a healthy immune response. Surprisingly, it comes from bacteria.

Trillions of commensal bacteria cover almost all environmentally exposed surfaces of our bodies at all times. But what are they doing? And why? If you want to understand the impact of commensal organisms on mammals, a good place to start is with mice that are devoid of all bacteria.

When I started working on this problem in 2002, so few people were still familiar with the germ-free mouse models that I had to persuade a retired research technician to help me set up sterile chambers and teach me the ways of “sanitary engineering.” Rather than the old steel and glass contraptions that he had used in his day (50 years ago), we were able to procure nicely modernized chambers with plastic bubbles that held up to four mouse cages. After my first few chamber contaminations, I began to understand why researchers rarely use germ-free animals.

Germ-free animals were conceived of almost a century ago, but were not successfully raised until 1945. James A. Reyniers’ group at the University of Notre Dame was the first to successfully raise and study germ-free animals. Perhaps reflecting a new fervor over hygiene, researchers concluded that wiping a mammal clean of microbes might actually be a good thing. The adult mice grew enormous bellies, stemming from digestive problems, but other than that, they seemed just as healthy and lived just as long as typical mice.

We inoculated a wild-type mouse with the bacterium H. hepaticus to create an experimental mouse version of the autoimmune disorder inflammatory bowel disease (IBD). H. hepaticus activates Th17 cells which release cytokines asociated with inflammation, like IL-17, causing symptoms of disease. But once B. fragilis expressing the polysaccharide A (PSA) is added to the gut, dendritic cells take up and present the PSA molecule on their surface, activating CD4 T cells and regulatory T cells(Tregs). The Tregs release IL-10 which suppresses the inflammatory action of IL-17, in effect alleviating IBD in mice.

When I trained as a microbiologist around the year 2000, the focus was still on pathogenic bacteria. But I became intrigued by the potential benefits of good bacteria. After all, we’ve coevolved with symbiotic bacteria for millions of years. The hygiene hypothesis, proposed in 1989 by David Strachan1, correlated lower environmental exposure to microbes—as seen in developed countries—with higher rates of allergies. The idea made sense to me. Commensal bacteria help keep pathogenic bacteria at bay, and in the late 1990s new research was beginning to show that symbionts also contribute to the development of the intestinal architecture. If bacteria were so crucial to development, what else might they do? Could they actually make us healthier? Challenging though it was, I was convinced the best way to learn about the systemic effects of bacteria was to start with mice that lacked them entirely.

Upon finishing my PhD in 2002 from the University of California, Los Angeles, I went to Dennis Kasper’s lab at Harvard Medical School. He was working on a prevalent commensal bacterium, Bacteroides fragilis. His lab had worked for years on the capsular polysaccharides that cover B. fragilis like hairs on a kiwi fruit. These surface carbohydrates are chains of repeating sugar molecules that function to give the bacteria a mucous-like barrier on its surface. Kasper had discovered that two of these eight polysaccharides have a unique zwitterionic structure: the molecules have both positive and negative charges on each repeating unit. While many bacteria are covered in polysaccharides, only a handful of species exhibit zwitterionic polysaccharides.

We inoculated a wild-type mouse with the bacterium H. hepaticus to create an experimental mouse version of the autoimmune disorder inflammatory bowel disease (IBD). H. hepaticus activates Th17 cells which release cytokines asociated with inflammation, like IL-17, causing symptoms of disease. But once B. fragilis expressing the polysaccharide A (PSA) is added to the gut, dendritic cells take up and present the PSA molecule on their surface, activating CD4 T cells and regulatory T cells(Tregs). The Tregs release IL-10 which suppresses the inflammatory action of IL-17, in effect alleviating IBD in mice.

When I arrived at Kasper’s lab, I wanted to learn more about these polysaccharides and their properties. I mutated the B. fragilis genes that are involved in the production of polysaccharides to express different combinations of the eight surface polysaccharides. I was able to delete seven of the eight polysaccharides by deleting the gene’s promoter region, but despite hundreds of attempts, I never generated a viable culture of bacteria that lacked all eight. It was clear that the bacteria needed this sugar coating for normal function, but I wondered whether the polysaccharides might also be important because they offered something that the mammalian host lacked. The lab had already shown that PSA—the most prevalent polysaccharide of the eight—stimulated T cells of the immune system in the test tube. They had tested B. fragilis’s other zwitterionic polysaccharide, PSB, but had found that its stimulatory effects paled in comparison to PSA. Whether PSA influenced the entire immune system of animals was a question that could only be asked in a controlled manner in germ-free mice.

The heyday of germ-free animal work was in the 1940s and 1950s. But recently other researchers dusted off the old germ-free mouse models and found problems beyond their big bellies and digestive troubles.

The heyday of germ-free animal work was in the 1940s and 1950s. But recently other researchers dusted off the old germ-free mouse models and found problems beyond their big bellies and digestive troubles.

The heyday of germ-free animal work was in the 1940s and 1950s. But recently, other researchers dusted off the old germ-free mouse models and found problems beyond their big bellies and digestive troubles. With new cellular and molecular tools, researchers demonstrated that these animals had serious problems with their immune systems: antibody deficiencies, higher susceptibility to infections, reduced number of Peyer’s patches and germinal centers (the locations of lymphocyte activity), less active intestinal macrophages and a reduced number and cytotoxicity of intestinal epithelial lymphocytes. In 1992, Lex Nagelkerken, at the TNO Institute of Ageing and Vascular Research in The Netherlands, had found that germ-free mice had a reduced number of CD4 T cells compared to conventionally colonized mice. CD4 T cells are critical for regulating the immune response, activating both cellular and antibody reactions. We decided to use CD4 T cell levels as a proxy marker for a healthy immune system in germ-free mice.

We colonized one group of germ-free mice with whole B. fragilis and another group with a strain of B. fragilis that lacked PSA but displayed the seven other polysaccharides. To my delight, wild-type B. fragilis restored CD4 T cell levels to those of animals with hundreds of bacteria. In mice that were colonized with the mutant bacteria lacking the zwitterionic PSA, CD4 T cell levels were no better than in germ-free mice.

This was an important result. Not only was a single strain of bacteria able to restore healthy levels of CD4 T cells, but we also identified the specific surface molecule that mediated these effects. I checked for an effect on other arms of the immune system: the CD8 T cells that can directly kill other cells, and the B cells, which produce antibodies. These cells appeared not to be affected. It looked like the bacteria with intact PSA were inducing CD4 T cells specifically.

When we looked at the histology of spleens, which, along with lymph nodes, serve as sites for the generation of immune responses, we saw that germ-free mice exposed to B. fragilis without PSA lacked the well-defined follicular structures that are a hallmark of healthy immune cell development. Mice colonized with wild-type B. fragilis contained follicles in abundance. It was the first evidence that bacteria might play a role in the development of organs other than the intestine.

To double-check the specific role of this molecule, I purified PSA from the surface of B. fragilis. When I fed the germ-free mice the polysaccharide, they developed conventional CD4 T cell levels—in the absence of all bacteria!

The next question was whether PSA was stimulating all CD4 T cells equally or if one of the two branches was activated preferentially. At the time, the “helper” CD4 T cells were divided into two classes depending on the cytokines they secreted: T-helper 1 (Th1) cells, which activate the cellular arm of the immune system, and T-helper 2 (Th2) cells, which activate the humoral or antibody-producing B-cells. The balance between Th1 and Th2 cells is important for the proper function of the immune system. When we investigated the Th profile of germ-free mice, we found that they had an abnormal balance of T-helper cytokines. Germ-free mice produce large quantities of interleukin-4 (IL-4)—a Th2 cytokine—and very little inteferon gamma (IFNγ)—aTh1 cytokine—compared to conventional mice. But germ-free mice colonized with B. fragilis restored IFNγ levels to normal and reduced Th2 cytokines. Purified PSA was able to restore Th1/Th2 balance to the entire organism. What seemed to be an intrinsic feature of a healthy immune system was in fact completely controlled by a single bacterial molecule.

Shortly after our findings were published2 an epidemiological study that extended the hygiene hypothesis caught my eye. The new study3 suggested that nonallergic autoimmune diseases such as multiple sclerosis, type 1 diabetes, and Crohn’s disease, were also on the rise in westernized societies. It occurred to me that there might be a possible role for B. fragilis in a wide range of immunologic diseases. The immune system is supposed to recognize foreign pathogens (such as bacteria) and eliminate them, while steering clear of healthy human cells. But sometimes the immune system can’t tell the difference between self and nonself, resulting in autoimmunity. One characteristic of this class of diseases is an imbalance in Th1/Th2 ratios, resulting in the immune system attacking host tissue. So if B. fragilis could correct a Th1/Th2 imbalance, perhaps it could also improve autoimmune diseases.

I began to appreciate that B. fragilis was “shaping” a coordinated and complex immune profile to promote intestinal health.

I began to appreciate that B. fragilis was “shaping” a coordinated and complex immune profile to promote intestinal health.

My autoimmune disease of choice was inflammatory bowel disease (IBD), a category of autoimmune disease that includes ulcerative colitis and Crohn’s disease in humans. Patients present symptoms that include abdominal pain, diarrhea, and rectal bleeding, caused by immune cell attack on the small or large intestine. These diseases affect about 2 million people in the United States, and that number is rapidly increasing. For decades, researchers had been looking for the pathogenic strains of bacteria responsible for IBD, to no avail. But several recent studies had pointed to the role of commensal—not pathogenic—bacteria in triggering IBD. With the benefits of B. fragilis in mind, I wondered: what if it wasn’t the presence of certain commensal bacteria triggering IBD, but the absence of protective symbiotic strains?

To test his hypothesis I colonized wild-type mice with B. fragilis, then induced IBD by introducing Helicobacter hepaticus—a bacterial strain known to initiate IBD in this experimental model. B. fragilis protected mice from IBD, but mice colonized with B. fragilis lacking PSA were not protected. The B. fragilis appeared to halt the autoreactive immune cells and prevent intestinal damage.

In 2006, I took an assistant professor position at California Institute of Technology. By then, researchers had discovered a new category of CD4 T cell that acted as a critical mediator of autoimmune diseases. This class of cells soon became all the rage in immunology circles. Th17 cells produce IL-17, a potent inflammatory T-cell cytokine associated with every known autoimmune disease. It became clear that immune reactions could actually be skewed toward Th1 (cellular), Th2 (humoral), or Th17 (autoimmune) pathways. Several studies found that Th17 reactions were involved in initiating IBD in mouse models. Was PSA inducing Th1 cytokines to shift the balance away from too much Th17 (and Th2)? If true, it would support my earlier study showing that PSA initiated the production of Th1 cytokines that reduced the higher Th2 response in germ-free mice. But what was the mechanism, and did PSA also suppress proinflammatory Th17 cells? I showed that PSA was still causing a proliferation of CD4 T cells, like in the germ-free mice of my earlier research, but also that another cell type called T regulatory cells was activated, and that it dampened inflammation by producing the cytokine IL-10. This cytokine was enough to suppress the pro-inflammatory IL-17 and protect the intestines from immune attack (see graphic above). I began to appreciate that B. fragilis was not inducing discrete immune responses such as Th1 cells, but was “shaping” a coordinated and complex immune profile to promote intestinal health.4

A few labs have recently been able to sequence the microbiota of healthy humans and IBD patients and showed dramatically reduced numbers of Bacteroidetes bacteria in IBD patients compared to healthy subjects. Currently, IBD patients are prescribed anti-inflammatory medicine, but this suppresses the entire immune system and puts the patient at a high risk of other illnesses and infections. In theory, B. fragilis as a probiotic therapy, or even administration of PSA alone, would have a more localized anti-inflammatory reaction in humans while cultivating the features of a functional immune system.

B. fragilis is certainly not the only important commensal bacterium in the human gut—it is merely the first one to be discovered with an immunomodulatory molecule. The Human Microbiome Project, an undertaking funded by the National Institutes of Health (NIH) to sequence the microbiota from hundreds of humans, has challenged itself with determining the relative quantities of all bacteria present in the human gut. With a known baseline of the bacteria present in healthy individuals, it will be much easier to understand which bacteria might be missing in diseased patients. Hopefully, the Human Microbiome Project will lead to the discovery of other beneficial bacteria.

For decades, scientists have been able to colonize germ-free animals with single organisms to evaluate their contributions to health. By pairing modern immunologic tools with these models, we’re starting to uncover truly novel effects of cohabitation with bacteria on human health.

Sarkis K. Mazmanian is an Assistant Professor in the Division of Biology at the California Institute of Technology. Sara W. McBride conducts research in Mazmanian’s lab.

References

1. D.P. Strachan, “Hay fever, hygiene, and household size,” BMJ, 299:1259–60, 1989.

2. S.K. Mazmanian et al., “An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system,” Cell, 122:107–18, 2005.

3. J.F. Bach, “The effect of infections on susceptibility to autoimmune and allergic diseases,” N Engl J Med, 347:911–20, 2002

4. S.K. Mazmanian et al., “A microbial symbiosis factor prevents intestinal inflammatory disease,” Nature, 453:620-25, 2008.

Lonza Group AG Submits Non-binding Proposal to Acquire All Patheon Inc. Restricted Voting Shares for USD 3.55 per Share, Significantly Above Existing Bid by JLL

• Proposal in line with Lonza’s stated strategy of expanding the offering across the pharmaceutical manufacturing value chain

• Lonza proposal significant improvement in value for Patheon shareholders

Basel, Switzerland and Toronto, Canada (August 21, 2009) – The Special Committee of Independent Directors of Patheon Inc. (TSX:PTI) and Lonza Group AG (SIX:LONN) announced today that Lonza, one of the world’s leading suppliers to the pharmaceutical, healthcare and life science industries, has submitted a non-binding proposal to acquire all of the outstanding Restricted Voting Shares of Patheon at a price of USD 3.55 per Restricted Voting Share.

“Our interest in Patheon is consistent with Lonza’s stated strategy of expanding our offering across the pharmaceutical manufacturing value chain. An acquisition of Patheon would take us into the complementary activities of finished dosage development and manufacturing for both small molecule and biological active ingredients. With Patheon, Lonza would be in a unique position to offer its customers manufacturing capability across the complete supply chain,” said Stefan Borgas, CEO of Lonza.

Paul Currie, Chairman of the Special Committee of Independent Directors of Patheon, said that, if completed, a transaction at the price proposed by Lonza would be a significant improvement in value for Patheon shareholders above the current offer from JLL Patheon Holdings LLC (“JLL”).

Lonza has signed a confidentiality and standstill agreement with Patheon. In turn, Patheon has also agreed not to negotiate an acquisition transaction with any party other than Lonza for a period ending September 30, 2009, subject to extension in certain circumstances. During this period, Lonza will be given additional access to information regarding Patheon so that it may complete its confirmatory due diligence. The terms of the exclusivity period permit Patheon to respond to an unsolicited superior acquisition proposal, subject to certain restrictions. The Lonza proposal does not commit either party to complete any transaction.

“Based on all of the information available to it, the Special Committee’s view has been that Patheon continuing as an independent company is a more attractive alternative than the JLL offer,” Mr. Currie said. “The Special Committee also believes that the Lonza proposal would provide an excellent opportunity to secure the successful future development of Patheon, and that it is in the best interest of all Patheon shareholders to explore the Lonza proposal further.”

The transaction contemplated by the Lonza proposal would be subject to Lonza being satisfied with the completion of its confirmatory due diligence investigations, the parties entering into definitive documentation, and the approval of each party’s Board of Directors. There can be no assurance that any such transaction will be completed or as to the terms of any such transaction.

About Lonza
Lonza is one of the world’s leading suppliers to the pharmaceutical, healthcare and life science industries. Its products and services span its customers’ needs from research to final product manufacture. Lonza is the global leader in the production and support of active pharmaceutical ingredients both chemically as well as biotechnologically. Biopharmaceuticals are one of the key growth drivers of the pharmaceutical and biotechnology industries. Lonza has strong capabilities in large and small molecules, peptides, amino acids and niche bioproducts which play an important role in the development of novel medicines and healthcare products. Lonza is a leader in cell-based research, endotoxin detection and cell therapy manufacturing. Lonza is also a leading provider of value chemical and biotech ingredients to the nutrition, hygiene, preservation, agro and personal care markets.

Lonza is headquartered in Basel, Switzerland and is listed on the SIX Swiss Exchange. In 2008, Lonza had sales of CHF 2.937 billion. Further information can be found at www.lonza.com.

About Patheon
Patheon Inc. (TSX:PTI; www.patheon.com) is a leading global provider of contract development and manufacturing services to the global pharmaceutical industry. Patheon prides itself in providing the highest quality products and services to more than 300 of the world’s leading pharmaceutical and biotechnology companies. Patheon’s services range from preclinical development through commercial manufacturing of a full array of dosage forms including parenteral, solid, semi-solid and liquid forms. Patheon uses many innovative technologies including single-use disposables, Liquid-Filled Hard Capsules and a variety of modified release technologies.

Patheon’s comprehensive range of fully integrated Pharmaceutical Development Services includes pre-formulation, formulation, analytical development, clinical manufacturing, scale-up and commercialization. Patheon can take customers direct to clinic with global clinical packaging and distribution services and Patheon’s Quick to ClinicTM programs can accelerate early phase development project to clinical trials while minimizing the consumption of valuable API.

Patheon’s integrated development and manufacturing network of 10 facilities, and seven development centers across North America and Europe, strives to ensure that customer products can be launched with confidence anywhere in the world.

these documents if and when they become available because they will contain important information about any such offer.

* Offer of $1.24/shr in cash or secured convertible notes

* Price represents 7 pct discount to Avigen’s Thurs close

* Sees deal closing in Q4

* Avigen shares fall 8 pct, MediciNova falls 4 pct (Recasts; adds details, share movement)

Biopharmaceutical company MediciNova Inc said it would buy embattled rival Avigen Inc., whose lead drug failed in a mid-stage trial last year, in a deal valued at about $37 million. The offer of $1.24 a share, in either cash or secured convertible notes, represents a 7 percent discount to Avigen’s Thursday close.

Avigen shares hit a low of $1.23 before recouping some losses to trade down 4 percent at $1.28 Friday morning on Nasdaq, while MediciNova shares were trading down 4 percent at $6.20.According to the terms, about $1.19 of the consideration will be paid to Avigen shareholders at the closing of the deal and about 5 cents will be paid on June 30, 2010, subject to certain adjustments. The secured convertible notes will be convertible on the final business day of each month into MediciNova common stock at $6.80 per share. In addition, Avigen stockholders will be entitled to one contingent payment right that will give them the right to receive certain other payments.

Avigen, which fell into tough times after its experimental drug for the treatment of spasticity associated with multiple sclerosis failed in a mid-stage trial last October, received an offer from MediciNova in December and the two companies reached an understanding in June on some key terms of the deal.

MediciNova, which is currently testing eight compounds in ten different indications, also has a multiple sclerosis drug called MN-166 in its pipeline.

The deal is expected to close in the fourth quarter, pending stockholder approvals.

RBC Capital Markets is acting as a financial advisor to Avigen, while Ladenburg Thalmann & Co is advising MediciNova, the companies said in a statement. (Reporting by Esha Dey in Bangalore; Editing by Anne Pallivathuckal)

© Thomson Reuters 2009.

TOKYO, August 21, 2009 – Astellas Pharma Inc. (“Astellas”; headquarters: Tokyo; President and CEO: Masafumi Nogimori) announced today that it has decided to reorganize its drug discovery research functions on October 1, 2009 as follows.
1. Creation of the Bioimaging Research Labs.
The Image Analysis Research Unit will be separated from the Applied Pharmacology Research Labs., and instead, the Bioimaging Research Labs. will be created in Tsukuba Research Center (Miyukigaoka) in order to carry out R&D projects more efficiently by using bioimaging technologies such as positron emission tomography (PET), magnetic resonance imaging (MRI) and X-ray CT which are widely used for clinical diagnosis and to promote closer cooperation with translational science experts and academia in Japan and abroad.

The Bioimaging Research Labs. will clarify the pharmacokinetic and pharmacological profile of new drug candidates, estimate their optimal doses and evaluate their pharmacological efficacy by fully utilizing various bioimaging technologies. Bioimaging technologies are also attracting increasing attention as a useful tool of translational science that can be effectively used to discover biomarkers that can be used to predict the efficacy in humans based on data related to pharmacological effects in animals. Through alliances and collaborative research programs with academia and other parties, the Bioimaging Research Labs. will promote the efficacy study, the synthesis of labeled compounds for new drug candidates, the development of automated apparatus for rapid synthesis of PET tracers, disease model animals and the support of clinical studies using bioimaging technologies.

2. Reorganization of fermentation research functions
The fermentation research functions of Tsukuba Research Center (Tokodai), will be reorganized as follows as of October 1, 2009 in order to build up a system that makes it possible to more agilely conduct drug discovery research more suitable for the target diseases and molecules by shifting weight from technology-based drug discovery approaches such as synthetic low molecules, natural products and antibody pharmaceuticals to more multiple approaches that organically combine all these technologies.

(1) Drug discovery research functions of the Fermentation Research Labs. will be transferred to the Pharmacology Research Labs. and the Molecular Medicine Research Labs. in order to ensure their more diversified development while maintaining their unique characteristics. In addition, platform technology functions that contribute to the construction of natural product library and the discovery of active products as new drug candidates will be transferred to Astellas Research Technologies Co., Ltd., a member of the Astellas Group. The Fermentation Research Labs. will be dissolved.

(2) All drug discovery functions, including fermentation research, at Tsukuba Research Center (Tokodai) will be transferred to Tsukuba Research Center (Miyukigaoka). For this purpose, a Fermentation Research Building (tentative) will be constructed in Tsukuba Research Center (Miyukigaoka) by the end of 2011.

Astellas is consolidating its technology platforms necessary to more efficiently develop antibody pharmaceuticals in addition to its traditional drug discovery research centered on synthetic low molecules and natural products in order to enhance its drug discovery functions necessary for the development of innovative new drugs. As part of this effort, Astellas created the Advanced Biologics Section that conducts exploratory research on antibody pharmaceuticals in its Molecular Medicine Research Labs. in October 2007 and acquired the US bioventure Agensys Inc. in December 2007. In addition, Astellas started construction of a new research building in Tsukuba Research Center (Miyukigaoka) in September 2009 in order to concentrate drug discovery research functions in Tsukuba area.

Astellas is committed to maximizing the efficiency of the drug discovery research process and further increasing the speed and quality of its drug discovery research.

J. Craig Venter Institute Researchers Clone and Engineer Bacterial Genomes in Yeast and Transplant Genomes Back Into Bacterial Cells

New methods allow for the rapid engineering of bacterial chromosomes and the creation of extensively modified bacterial species; should also play key role in boot up of synthetic cell

ROCKVILLE, Md., Aug. 20 /PRNewswire-USNewswire/ — Researchers at the J. Craig Venter Institute (JCVI), a not-for-profit genomic research organization, published results today describing new methods in which the entire bacterial genome from Mycoplasma mycoides was cloned in a yeast cell by adding yeast centromeric plasmid sequence to the bacterial chromosome and modified it in yeast using yeast genetic systems. This modified bacterial chromosome was then isolated from yeast and transplanted into a related species of bacteria, Mycoplasma capricolum, to create a new type of M. mycoides cell. This is the first time that genomes have been transferred between branches of life — from a prokaryote to eukaryote and back to a prokaryote. The research was published by Carole Lartigue et al in Science Express.

Hamilton Smith, M.D

Hamilton Smith, M.D., one of the leaders of the JCVI team said, “I believe this work has important implications in better understanding the fundamentals of biology to enable the final stages of our work in creating and booting up a synthetic genome. This is possibly one of the most important new findings in the field of synthetic genomics.”

The research published today was made possible by previous breakthroughs at JCVI. In 2007 the team published results from the transplantation of the native M. mycoides genome into the M. capricolum cell which resulted in the M. capricolum cell being transformed into M. mycoides. This work established the notion that DNA is the software of life and that it is the DNA that dictates the cell phenotype.

In 2008 the same team reported on the construction of the first synthetic bacterial genome by assembling DNA fragments made from the four chemicals of life–ACGT. The final assembly of DNA fragments into the whole genome was performed in yeast by making use of the yeast genetic systems. However, when the team attempted to transplant the synthetic bacterial genome out of yeast into a recipient bacterial cell, all the experiments failed.

The researchers had previously established that no proteins were required for chromosome transplantations, however they reasoned that DNA methylation (a chemical modification of DNA that bacterial cells use to protect their genome from degradation by restriction enzymes, which are the proteins that cut DNA at specific sites) might be required for transplantation. When the chromosome was isolated direct from the bacterial cells it was likely already methylated and therefore transplantable due to it being protected from the cells restriction enzymes.

In this study, the team began by cloning the native M. mycoides genome into yeast by adding a yeast centromere to the bacterial genome. This is the first time a native bacterial genome has been grown successfully in yeast. Specific methylase enzymes were isolated from M. mycoides and used to methylate the M. mycoides genome isolated from yeast. When the DNA was methylated the chromosome was able to be successfully transplanted into a wild type species of M. capricolum. However, if the DNA was not first methylated the transplant experiments were not successful. To prove that the restriction enzymes in the M. capricolum cell were responsible for the destruction of the transplanted genome the team removed the restriction enzyme genes from the M. capricolum genome. When genome transplantations were performed using the restriction enzyme minus recipient cells, all the genome transplantations worked regardless of if the DNA was methylated or not.

“The ability to modify bacterial genomes in yeast is an important advance that extends yeast genetic tools to bacteria. If this is extendable to other bacteria we believe that these methods may be used in general laboratory practice to modify organisms,” said Sanjay Vashee, Ph.D., JCVI researcher and corresponding author on the paper.

The team now has a complete cycle of cloning a bacterial genome in yeast, modifying the bacterial genome as though it were a yeast chromosome and transplanting the genome back into a recipient bacterial cell to create a new bacterial strain. These new methods and knowledge should allow the team to now transplant and boot up the synthetic bacterial genome successfully.

The research published today by JCVI researchers was funded by the company Synthetic Genomics Inc., a company cofounded by Drs. Smith and Venter.

Key Milestones/Ethical Issues Background on JCVI’s Synthetic Genomics Research

1995: After sequencing the M. genitalium genome (published in 1995), Dr. Venter and colleagues begin work on the minimal genome project. This area of research, trying to understand the minimal genetic components necessary to sustain life, started with M. genitalium because it is a bacterium with the smallest genome known that can be grown in pure culture. This work was published in the journal Science in 1999.

2003: Drs. Venter, Smith and Hutchison (along with JCVI’s Cynthia Andrews-Pfannkoch) made the first significant strides in the development of a synthetic genome by assembling the 5,386 base pair genome of bacteriophage phi X174 (phi X). They did so using short, single strands of synthetically produced, commercially available DNA (known as oligonucleotides) and using an adaptation of polymerase chain reaction (PCR), known as polymerase cycle assembly (PCA), to build the phi X genome. The team produced the synthetic phi X in just 14 days.

2007: JCVI researchers led by Carole Lartigue, Ph.D., announced the results of work published in the journal Science, which outlined the methods and techniques used to change one bacterial species, Mycoplasma capricolum, into another, Mycoplasma mycoides Large Colony (LC), by replacing one organism’s genome with the other one’s genome. Genome transplantation was the first essential enabling step in the field of synthetic genomics as it is a key mechanism by which chemically synthesized chromosomes can be activated into viable living cells.

January 2008: The second successful step in the JCVI teams’ journey to create a cell controlled by synthetic DNA was completed when Gibson et al published in the journal Science, the synthetic M. genitalium genome.

December 2008: Gibson et al published a paper in Proceedings of the National Academy of Sciences (PNAS) describing a significant advance in genome assembly in which the team was able to assemble in yeast the whole bacterial genome, Mycoplasma genitalium, in one step from 25 fragments of DNA. The work was funded by the company Synthetic Genomics Inc. (SGI). The team is still working to boot up the synthetic cell using all the knowledge gleaned from their previous work.

Ethical Considerations:

Since the beginning of the quest to understand and build a synthetic genome, Dr. Venter and his team have been concerned with the societal issues surrounding the work. In 1995 while the team was doing the research on the minimal genome, the work underwent significant ethical review by a panel of experts at the University of Pennsylvania (Cho et al, Science December 1999:Vol. 286. no. 5447, pp. 2087 – 2090). The bioethical group’s independent deliberations, published at the same time as the scientific minimal genome research, resulted in a unanimous decision that there were no strong ethical reasons why the work should not continue as long as the scientists involved continued to engage public discussion.

Dr. Venter and the team at JCVI continue to work with bioethicists, outside policy groups, legislative members and staff, and the public to encourage discussion and understanding about the societal implications of their work and the field of synthetic genomics generally. As such, the JCVI’s policy team, along with the Center for Strategic & International Studies (CSIS), and the Massachusetts Institute of Technology (MIT), were funded by a grant from the Alfred P. Sloan Foundation for a 20-month study that explored the risks and benefits of this emerging technology, as well as possible safeguards to prevent abuse, including bioterrorism. After several workshops and public sessions the group published a report in October 2007 outlining options for the field and its researchers.

About the J. Craig Venter Institute

The JCVI is a not-for-profit research institute in Rockville, MD and La Jolla, CA dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 400 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The legacy organizations of the JCVI are: The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), the Institute for Biological Energy Alternatives (IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science Foundation. The JCVI is a 501 (c) (3) organization. For additional information, please visit http://www.jcvi.org/ [1]

J&J Vice Chairman Christine Poon

Top executives from several leading pharma companies made Forbes‘ “The World’s Most Powerful Women” list. The annual feature ranks women based on visibility in the

Sheri McCoy

media and organization or country size. This year’s list includes Johnson and Johnson’s Sherilyn McCoy at 65th, GlaxoSmithKline’s Deirdre Connelly at 73rd, Pfizer’s Amy Schulman at 80th, and Melanie Healey of Proctor & Gamble at 83rd.

Sheri McCoy was promoted to worldwide president of the company’s pharmaceutical group last October, replacing the “most powerful woman in pharma,”

Christine Poon . A J&J veteran of more than 25 years, McCoy previously served as chief of the company’s surgical products division, its medical devices unit in Latin America and the pharma giant’s subsidiary, Ethicon. McCoy’s a chemical engineer by training, with degrees from the University of Massachusetts-Dartmouth and Princeton University. She also received an M.B.A. from Rutgers University.

Deirdre Connelly

In January, Deirdre Connelly left Eli Lilly, where she was president of U.S. operations, to join GlaxoSmithKline as North American pharmaceuticals chief. Connelly had joined Lilly in 1983 and worked hard to move up the ladder, eventually earning the position of chief U.S. ops in 2005. She received her B.A. in economics and marketing at Pennsylvania’s Lycoming College and graduated from Harvard’s Advanced Management Program in 2000.

Amy Schulman

Amy Schulman took the reins as Pfizer’s general counsel in May of 2008, after Allen Waxman left for personal reasons. Prior to her appointment as GC, this premier litigat

or was a partner at the law firm DLA Piper where she specialized in product liability cases. She received her law degree from Yale University, following in the footsteps of her father, Alvin H. Schulman, a partner at Moses & Singer in New York and her grandfather, the late Edward Weinfeld, a longtime judge for the Southern District of New York.

Melanie Healey

Melanie Healey joined Proctor & Gamble in 1990 as a brand manager for P&G’s Phebo Soap and continued to develop a career in marketing from there. The Brazilian native landed the position of president of Proctor & Gamble’s feminine and health care division in 2007. She holds a B.S. in business administration from the University of Richmond.

Look out for our feature profiling influential women in pharma coming later this year. Have a name you’d like to throw in the hat? Let us know.

Company Leading Innovation in Colorectal Surgery

Naarden, The Netherlands, 13 August 2009 – Forbion Capital Partners today announced that acting as lead investor it successfully closed an $18.5 million series F of NiTi™ Surgical Solutions, an innovative surgical device company. Existing investors also participated in the financing, including: Evergreen Venture Partners, Israel Healthcare Ventures (IHCV), MBVC and Alice Lab, and SCP Vitalife. In conjunction with this closing, Avi Molcho, MD, venture partner at Forbion, will join NiTi’s Board of Directors.

NiTi (Chesterfield, MO, USA) will use the proceeds from this financing to support the marketing and roll-out of the company’s ColonRing™ and to advance research and development of other BioDynamix™ Anastomosis Technology programmes.

The ColonRing is a revolutionary closure technology for surgeries such as colon cancer surgery and has been successfully applied in over 2,200 patients. It was recently launched in the US, and the device has been very well received by users due to its excellent wound healing capabilities.

“NiTi offers a compelling investment thesis for us with its unique BioDynamix Anastomosis Technology platform and strong clinical support from leading surgeons across the globe,” stated Dr. Molcho. “We truly believe that NiTi’s technology, starting with the recently launched ColonRing, offers surgeons a revolutionary approach to anastomosis that will permanently change the current surgical paradigm for the better.”

“This successful financing is a direct result of NiTi Surgical Solutions’ well-executed business strategy and growing market presence in anastomosis, with its proprietary BioDynamix Technology,” stated Hadar Ron, MD, managing director of IHCV and chairman of the Board of Directors for NiTi. “By successfully developing and commercialising much-needed, state-of-the-art medical devices to optimise surgical

outcomes for patients, NiTi is emerging as a significant player in the surgical closure technology market.”

NiTi Surgical Solutions’ shape memory surgical rings, clips, and appliers represent the next generation in internal tissue-closure devices. These advanced devices are designed for treatment of colorectal, gastric and upper gastrointestinal disease requiring surgical anastomosis. The company`s unique line of products utilise nitinol-based elements to press together the ends of resected tissue, enabling natural reconnection and healing of the intestine after removing a section as part of a surgery, such as in colon cancer treatment.

The company’s FDA-cleared, CE-marked ColonRing™ represents the first major advancement in colorectal surgery in more than 30 years and addresses the significant drawbacks of traditional staples.

“NiTi’s ability to garner additional financing from leading biotech investors underscores the strength and utility of our proprietary technology, and the promise and potential for our products to meet the critical needs of surgeons, physicians, and patients,” said Itay Itzhaky, chief executive officer of NiTi Surgical Solutions. “Our first marketed product, the novel ColonRing with BioDynamix Anastomosis Technology, is one of several innovative nitinol devices we expect to bring to market. This recent round of financing will help us broaden our sales and marketing presence, as well as further our research and development activities to support a variety of advanced surgical products in the coming months.”

Last week, the company signed a distribution deal for its microRNA diagnostic kits in Canada.

Gali Weinreb

MicroRNA-based molecular diagnostics developer Rosetta Genomics Ltd. (Nasdaq:ROSG) today signed its fourth international distribution agreement. The new agreement is with India’s Super Religare Laboratories Ltd. (SRL), which will distribute Rosetta’s three currently-available miRview diagnostic tests in India, Saudi Arabia, Qatar, and the UAE. SRL will send the samples to Rosetta Genomics’ Philadelphia-based CLIA-certified laboratory for analysis.

SRL is one of India’s largest diagnostic laboratories, handling samples from seven million patients a year. The three tests are the miRview mets, which can accurately identify the primary tumor site, even when a tumor has not been identified; the miRview squamous, which uses a single microRNA to differentiate squamous from non-squamous, non-small cell lung cancer patients; and the miRview meso, which differentiate mesothelioma, a cancer connected to asbestos exposure, from other lung cancers.

Rosetta and SRL are considering expanding their relationship into R&D projects.

Last week, Rosetta signed an exclusive distribution agreement for the three tests in Canada with Warnex Inc. (TSX: WNX) Warnex Medical Laboratories. Warnex will also send the samples to Rosetta’s Philadelphia laboratory.

Rosetta chief commercialization officer Ronen Tamir noted that the deals follow the distribution agreements with Prometheus Laboratories in the US, and with Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA; TASE: TEVA) in Israel and Turkey.

Rosetta’s share rose 0.6% at the opening on Nasdaq today to $3.15, giving a market cap of $44 million.

Published by Globes [online], Israel business news – www.globes-online.com – on August 20, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

LONDON, Aug 25 (Reuters) – A sexually transmitted virus that causes cervical cancer is also to blame for half of all cases of cancer of the penis, Spanish researchers said on Tuesday.

The finding suggests already available human papillomavirus (HPV) vaccines for cervical cancer are also likely to be effective in the fight against penile cancer, doctors from the Catalan Institute of Oncology in Barcelona said.

Merck & Co’s Gardasil and GlaxoSmithKline’s Cervarix are both used widely to immunise girls against HPV infection, which can lead to cancer of the cervix.

Penile cancer is much rarer, accounting for less than 1 percent of adult male cancers in Europe and North America, although the incidence can be as high as 10 percent in parts of Africa and Asia. Worldwide, there are more than 26,000 new cases every year.

Dr. Silvia de Sanjose and colleagues reviewed cases of penile cancer reported in clinical studies between 1986 and 2008 and found 46.9 percent of tumours were associated with HPV.

Nearly all of these were linked to HPV strains 16 and 18, the two types that most commonly cause cervical cancer and which are targeted by Gardasil and Cervarix, they wrote in the Journal of Clinical Pathology.

Merck reported results of a clinical trial last November showing that Gardasil was effective in preventing lesions caused by the virus in men. [ID:nN13347832] (Reporting by Ben Hirschler; Editing by Victoria Main)

Irish drugmaker Warner Chilcott PLC said Monday it would buy Procter & Gamble Co.’s prescription drug business for $3.1 billion.

Warner Chilcott, which specializes in women’s health and dermatology products, would receive a portfolio with $2.3 billion in annual sales, boost its offerings with a blockbuster osteoporosis treatment and obtain a toehold in the urology and gastroenterology markets.http://ir.wcrx.com/common/alerts/WCRX/default/logo.gif

The deal also would bring the Ardee, Ireland, company an unspecified number of Procter & Gamble’s prescription drugs in development and manufacturing facilities in Puerto Rico and Germany.

Just the top drug that Warner Chilcott receives in the deal, Actonel for osteoporosis, with more than $1 billion in annual sales, exceeds the company’s 2008 revenue of $938 million. Warner Chilcott also gains colitis drug Asacol HD, bone drug Didronel and Enablex for overactive bladder.

The deal is in line with P&G’s recent strategy of shedding products to focus on areas with the best growth and profit-margin prospects.

Last year, P&G sold another billion-dollar brand, Folgers coffee, to J.M. Smucker Co. for roughly $3 billion. Last month, it sold Japanese market rights for its osteoporosis treatment to Ajinomoto Co. for $210 million.

“We know that our shareholders don’t reward us … for absolute size; they reward us for growth,” Chief Executive Bob McDonald said in a conference call.

Copyright © 2009, Chicago Tribune

www.chicagotribune.com/news/chi-ctshare..templatelibrary.biz.ar7aug25,0,225714.story

By CAMILLE RICKETTS of VentureBeat

Complete Genomics, provider of supposedly cheaper and faster DNA sequencing services, has raised $45 million in a fourth round of funding — a huge amount for a biotech company in today’s economic environment. Based in Mountain View, Calif., the company says it will be able to sequence people’s genes in only a few days, and for the bargain price of $5,000.

Apparently, genetic companies are where its at in the life science market right now. Earlier this month, Pacific Biosciences, another firm looking to speed sequencing practices, commanded a large $68 million in new financing from Wellcome Trust, Monsanto, Sutter Hill Ventures and others.

The money will be used to set up a facility for large-scale sequencing project, slated to open by the beginning of 2010, the company says. The goal is to sequence 10,000 human genomes in the next year at this center. If it does achieve the lower price tag — down from the typical price of between $100,000 and $350,000 — Complete Genomics could achieve the same commercial success as 23andMe, Navigenics and deCODE, startups that also read customers’ DNA, while providing even more in-depth information.

That being said, the company won’t be targeting the consumer market at first, opting instead to sell to pharmaceutical companies, laboratories and other companies that want to refine their genetic testing practices. One such company, called Knome, completely sequences its customers’ genomes for the astronomical price of $350,000. Some reports say Knome is in licensing talks with Complete Genomics to bring its price point down and broaden its appeal.

Essex Woodlands Health Ventures, OrbiMed Advisors, Enterprise Partners Venture Capital, OVP Venture Partners, Prospect Venture Partners and Highland Capital Management provided the recent round of funding. The company has raised $90 million to date.

Copyright 2009 VentureBeat. All Rights Reserved.

By D.C. Denison, Globe Staff

Biopure Corp., the Cambridge firm that was working on developing a human blood substitute, has concluded the previously announced auction of substantially all of its assets in connection with its bankruptcy. OPK Biotech LLC, a Delaware company, will purchase Biopure’s operating assets for slightly over $4 million. OPK also agreed to purchase Biopure’s 50 percent interest in a partnership that owns the Cambridge building that houses Biopure’s headquarters, and some laboratory space, for $850,000. Both sales are expected to close within 30 days.

A product of Biopure Corp.

“This is the end of the road for Biopure,” said Biopure chief executive Zafiris G. Zafirelis today.

The ambitious biotech firm, which declared Chapter 11 bankruptcy last month, was once one of the state’s most promising biotechs. Hemopure, made from cow hemoglobin, long seemed on the verge of emerging as a potential life-saving breakthrough. But Biopure could never clear regulatory hurdles that would have turned Hemopure into a mainstream medical product.

Hemopure showed many benefits compared with real blood: a three-year shelf life, the ability to be used by patients of any blood type, and freedom from diseases and pathogens that could be transmitted by human blood.

The path to Food and Drug Administration approval, however, was rocky. Although the Navy was interested in using the experimental product to treat military personnel wounded in battle, where traditional blood transfusions aren’t readily available, the FDA consistently rejected Biopure and the Navy’s efforts to test the product in clinical trials, citing safety worries and other concerns.

In a regulatory filing, Biopure said it does not expect that Biopure stockholders will receive any substantial money resulting from the sale to OPK.

Biopure chief executive Zafirelis said “I’m hoping that OPK Biotech will continue to develop Biopure’s products.”

A new study by researchers at the University of Iowa Hospitals and Clinics found that thigh muscle strength does not predict the occurrence of knee osteoarthritis (OA) uncovered in x-rays, but does predict incidence of painful or stiff knee OA. Women with the strongest quadriceps muscles appeared to be protected against the development of knee OA symptoms. Details of this study appear in the September issue of Arthritis Care & Research, a journal published by Wiley-Blackwell on behalf of the American College of Rheumatology.

The knee is the most common weight-bearing joint affected by osteoarthritis or degenerative joint disease, a major cause of disability in the U.S. The Centers for Disease Control and Prevention (CDC) estimate that

26.9 million U.S. adults are affected by OA with 16% (aged 45+ years) of those cases occurring in the knee. Approximately 18.7 % of symptomatic knee OA patients are female and 13.5% are male. A Medical Expenditure Panel Survey estimates that total out-of-pocket expenditures for treatment of arthritis was $32 billion in 2005.

Neil Segal, M.D., M.S., and colleagues in a study funded by the National Institute on Aging followed 3,026 men and women ages 50-79 over a 30-month period in the Multicenter Knee Osteoarthritis Study (MOST) to assess whether knee extensor strength would predict incident radiographic (OA that can be determined through X-ray) or symptomatic knee OA. Of those enrolled, a total of 2,519 knees were included in the study of radiographic knee OA and 3,392 knees were evaluated for the combination of radiographic OA and symptoms of OA that include pain, aching or stiffness on most days of the month.

Participants were evaluated for thigh muscle strength using an isokinetic dynamometer, a device that measures the strength of different muscle groups. The balance of muscle strength between quadriceps and hamstrings (H:Q ratio) was used to assess weakness in the lower extremity musculature. X-rays of the knees were taken at the onset of the study and the conclusion to determine the presence of OA. A telephone screen at the beginning and end of the study was conducted to establish if frequent pain, aching or stiffness was present in the knee. Data on height, weight (Body Mass Index-BMI), femoral neck bone mineral density (BMD), and physical activity status was also collected from participants.

By the conclusion of the study 48 of 680 men and 93 of 937 women developed OA detected by x-ray. At the end of the 30-month period 10.1% of women and 7.8% of men displayed signs of symptomatic knee OA. “Our results showed thigh muscle strength was not a significant predictor of radiographic knee OA,” concluded the authors. Women in the top third of peak knee extensor strength had a lower incidence of symptomatic knee OA, while men with strong thigh muscles had only slightly better odds of developing OA symptoms compared to men with weaker knee extensor strength. “The H:Q ratios were not predictive of

symptomatic knee OA in either men or women,” added researchers.

Researchers acknowledge there to be some limitation to the study by not including assessments of hip abductor strength. “Study of hip abductor strength, which is important for control of the knee joint, may be useful in a more comprehensive study of risk for OA of the knee,” said Dr. Segal. “These findings suggest that targeted interventions to reduce risk for symptomatic knee OA could be directed toward increasing knee extensor strength,” he added.

Article: “Effect of Thigh Strength on Incident Radiographic and Symptomatic Knee Osteoarthritis in a Longitudinal Cohort,” Neil A. Segal, James C. Torner, David Felson, Jingbo Niu, Leena Sharma, Cora E. Lewis, Michael Nevitt. Arthritis Care & Research; Published Online: August 27, 2009 (DOI 10.1002/art); Print Issue Date: September 15, 2009.

Fairfield, CT – (August 24, 2009) – Competitive Technologies, Inc. (NYSE Amex: CTT) announced today that it has added the prestigious University of Miami Pain Management Center to the list of organizations to use its pain therapy medical device. The University will utilize the device to treat patients at the University of Miami Pain Management Center that is under the direction of Dr. Salahadin Abdi, MD, PhD, Professor and Chief, University of Miami Pain Management Center, and Dr. David A. Lubarsky, MD, Professor and Chairman of the Department of Anesthesiology, Perioperative Medicine and Pain Management at the University of Miami School of Medicine.

“This non-invasive pain therapy medical device treats pain without the harmful side effects of narcotic painkillers,” said John B. Nano, CTT’s Chairman, President and CEO. “Cleared for use by the U.S. Food and Drug Administration (FDA) and the European Union, the device provides rapid treatment of high-intensity oncologic and neuropathic pain, including pain resistant to morphine and other drugs.

“This device brings CTT to the forefront in providing a solution to the needs of patients and the improvement of palliative healthcare in the U.S. and globally. It is a prime example of our strategy to connect clinical science to patient care. This medical device has successfully treated over 3,000 patients in Europe and dozens of patients in the U.S. at hospitals and pain therapy centers. CTT’s pain therapy medical device is currently being used by clinical investigators at the Virginia Commonwealth University Massey Cancer Center for independent clinical research to examine the device’s ability to decrease pain associated with chemotherapy-induced peripheral neuropathy (CIPN). Principal investigator Thomas J. Smith, MD, is an international leader in palliative care and pain management, and Patrick Coyne, APRN, MSN, is co-investigator. The device has been used to successfully treat over 20 wounded warriors at the Walter Reed Army Medical Center. The treatments were for pain from loss of limb, back injuries, and other neuropathies.Text Box: www.competitivetech.net/pain.html”

“Several studies report that nearly 10% of adults in the U.S. suffer from moderate-to-severe pain, with over 50% experiencing chronic or recurrent pain,” said Aris D. Despo, CTT’s Executive VP, Business Development. “The U.S. market for prescription pain drugs, the prevailing treatment for pain management, is nearly $5.0 billion, with nearly half for treatment of cancer pain, and about 40% for orthopedic pain, including lower back pain. Our device also treats neuropathic pain, the result of nerve damage, which is difficult to treat with traditional pain medications.”

For more information on the device, visit www.CalmareTT.com.

About The University of Miami, Pain Management Center

The UM Pain Management Center is the leading multidisciplinary pain management facility in the southeastern U.S. State-of-the-art pain relief treatment and education are offered to patients from all over the world. Cutting edge research is conducted to seek new treatment for refractory pain conditions.

The Center, with three clinics in the South Florida area, is dedicated to excellent patient care, teaching and research to discover new ways to relieve pain. For more information visit: http://umdas.med.miami.edu/x33.xml

About Competitive Technologies, Inc.

Competitive Technologies, established in 1968, provides distribution, patent and technology transfer, sales and licensing services focused on the needs of its customers and matching those requirements with commercially viable product or technology solutions. CTT is a global leader in identifying, developing and commercializing innovative products and technologies in life, electronic, nano, and physical sciences developed by universities, companies and inventors. CTT maximizes the value of intellectual assets for the benefit of its customers, clients and shareholders. Visit CTT’s website: www.competitivetech.net

Scientists have discovered a way of allowing healthy cells to take charge of cancerous cells and stop them developing into tumours in what could provide a new approach to treating early-stage cancers.

University of Manchester researchers found that a special type of the chemicals known as ‘kinase inhibitors’ opened up communication channels on the surface of cells that enabled healthy cells to ‘talk’ to the cancer cells.

“When we added the chemicals to a mixture of healthy and cancerous cells in a flask the diseased cells stopped multiplying and began acting like normal cells again,” said Dr Ian Hampson, who carried out the research with wife Dr Lynne Hampson.

“Further tests revealed that the chemicals helped the cancer cells form connections with surrounding healthy cells that allowed these normal cells to take charge of the mechanism by which cancer cells divide and grow out of control.”

Cell division occurs naturally and continuously in human organs and tissue as part of the body’s normal repair processes to combat wear and tear but in cancer the cells divide in an uncontrolled way.

Dr Hampson says the findings, published in the British Journal of Cancer, are all the more exciting because the chemicals, which were developed with colleagues at the University of Salford, appear to be relatively non-toxic and the positive effect on the cancer cells persists even when the chemicals are withdrawn.

“When the chemicals were added to a culture containing just cancer cells they had little effect,” said Dr Hampson, who is based in Manchester’s School of Cancer and Imaging Sciences. “It was only when we added the chemicals to a mixture of cancer cells and normal cells – similar to how you would find them in the body – that growth was suppressed.

“Intriguingly, the connections that allowed the healthy cells to communicate with the cancer cells stayed open even when the kinase inhibitors were removed indicating that a potential drug based on these chemicals could be given as a short course of treatment.

“Furthermore, the chemicals are non-poisonous and do not actually kill cells like conventional cancer therapies, such as chemotherapy and radiotherapy, so if we were able to develop a drug it is likely to have far fewer side-effects.”

The team say the next stage of their research will be to find out exactly how the chemicals are able to increase the number of connections between cancer and normal cells. Once this is known, it should be possible to produce a drug based on these chemicals that could hopefully be used in humans.

Dr Lynne Hampson added: “We are currently applying for funding to carry out further research into the biochemistry of how these chemicals cause the effect we have observed. We also intend to investigate the use of different types of cell cultures to assess the potency and range of activity of these agents.”

The research was funded by the Association for International Cancer Research, The Humane Research Trust, The Caring Cancer Research Trust, Kidscan and the Cancer Prevention Research Trust.

Contact: Aeron Haworth, Media Relations, Medical and Human Sciences, The University of Manchester, Tel: 0161 275 8383, Email: aeron.haworth@manchester.ac.uk

Source: The University of Manchester

VARIOUS pieces of legislation now making their way through Congress would require private pools of investment capital to be registered with the Securities and Exchange Commission. The goal is to curtail abuses and protect the public from questionable practices. The proposed laws would cover the range of funds that deal in derivatives, auction-rate and mortgage-backed securities, highly leveraged transactions and a slew of other instruments so complicated as to defy description.

In registering, these funds would need to open their books to the government so that they could be duly monitored, thus limiting further risks to the financial system.

Unfortunately, however, with good intentions, the Obama administration and some members of Congress are aiming this legislation at all pools of private capital. That includes venture-capital funds, which pose no systemic risks and which, especially now, should be kept free of any new reporting rules and allowed the freedom to flourish.

Venture-capital funds deal solely with privately purchased equity securities in start-up companies, which are not traded in public markets. They have as their limited partners only people who meet the S.E.C.’s definition of a “qualified client” (meaning they possess a substantial amount of money to invest). These investors, who typically allocate a small percentage of their portfolios to venture capital, are familiar with risk, but it is long-term risk, stretching out 7 to 10 years. They put their faith not in publicly traded securities but in entrepreneurs, emerging technologies and new markets.

Because their business is contained within the ecosystem of limited partners, venture-capital funds and the companies in which they invest absorb all the risk: there can be no domino effect in the world financial system.

Venture-capital funds do not leverage investments with debt either, so they’re not tied to commercial banks. They don’t sell short, trade in public securities or employ any hedging techniques.

These funds already comply with Securities and Exchange Commission requirements for reporting of private offerings on Form D. This information is adequate to allow the government to keep track of an industry that, with less than $200 billion under management, makes investments that amount to no more than 0.2 percent of gross domestic product. Venture-capital funds also comply with all rules for the private placement of securities and the formation of private, unregistered investment funds, including screening investors for suitability.

The venture-capital industry has been the target of new regulations before and has experience with unintended consequences. The better part of this decade has been spent working through those created by the Sarbanes-Oxley Act of 2002, which was meant to curb accounting abuses at large corporations like Enron but ended up imposing burdensome accounting rules on small, often venture-backed companies. One section of that law, which was meant to get large corporations to lay bare their accounting practices, has cost these small companies millions of dollars a year in labor, extra audit fees and external consulting expenses.

A side effect of Sarbanes-Oxley has been to discourage initial public offerings, reducing the amount of expansion capital available for start-up companies. Indeed, the number of venture-backed public offerings, which reached 1,353 from 1991 to 1997, declined to 392 from 2001 to 2008.

It would be a shame to impose any new limits now, when venture capital is the asset class that can best help build and nurture the companies that bring about growth and job creation. The figures are compelling. In 2008, venture-backed companies that went public in previous years accounted for 12.1 million jobs and $2.9 trillion in revenues for the United States Treasury.

The names of companies financed by venture capital are legendary: Cisco, Google, Facebook, Apple, Federal Express, Staples, Yahoo, Amazon, Genentech and on and on. The privately purchased equity securities that helped start these companies supported new technological and scientific ideas, all of which led to new jobs.

Expanded regulation in financial services is inevitable and in some instances necessary. But at a time when venture capital for young companies is already squeezed by the recession, and when the economy is in serious need of new jobs, Congress should find ways to stimulate, not risk hindering, the formation of venture capital.

Merck CEO Announces Structure and Global Leadership Team for New Merck

New Structure to Capitalize on Growth Opportunities in Emerging Markets, Biologics, Vaccines, Animal Health and Consumer Health Care

Merger Planning on Track; Expected to Close in Fourth Quarter

New Merck Organized to Maximize Broader Product Portfolio With a Robust R&D Pipeline to Better Meet Patient Needs

WHITEHOUSE STATION, N.J., Aug. 31, 2009 – Richard T. Clark, chairman, president and chief executive officer of

Richard T. Clark, Merck's CEO

Merck & Co., Inc. (NYSE: MRK) today announced a new organizational structure and named top management and senior leaders for the new Merck effective upon completion of the merger of Merck & Co., Inc. and Schering-Plough Corporation (NYSE: SGP).  Mr. Clark was named CEO of the combined company when the merger agreement was signed in March.

The new structure will build on the combined strengths of Merck and Schering-Plough to create a more customer-focused, innovative and diversified global health care company positioned to capitalize on the greatest opportunities for growth.  Animal Health and Consumer Health Care will operate as separate business units reporting to Mr. Clark.

The new company will integrate across its divisions to take advantage of the significant growth opportunities in three key areas: emerging markets, biologics and vaccines.  This cross-divisional approach will ensure that the new Merck’s commercial, research and manufacturing divisions dedicate the focus and resources necessary to become a leader in these businesses.

The organizational structure for the new Merck is designed to capture the opportunities in the broader and deeper in-line pharmaceutical franchises that will be created through the integration of Merck and Schering-Plough products.  The company also will create new franchises focused on Women’s Health and Endocrine, and Mature Brands.

Kenneth C. Frazier

The new Merck will benefit from the unparalleled industry experience of senior leaders from both Schering-Plough and Merck.  The leaders named by Mr. Clark today will serve on the company’s new Executive Committee.  They, in turn, named the executives who will lead their divisional and functional teams at the new Merck.  About 40 percent of Schering-Plough’s senior leaders will be part of the newly combined company in executive roles.  As was indicated at the time of the merger announcement last March, a substantial majority of Schering-Plough employees will remain with the combined company.

“Today’s announcement is an important step in establishing the new Merck as the leading global health care company – one that will make a difference in the lives of patients around the world,” said Mr. Clark.  “The combined company will draw upon the expertise of the people of both Schering-Plough and Merck.  Collectively, the new leadership team has decades of industry experience and proven management track records.  To complement our joint talent, we will be adding leaders from outside the two companies with specific experience in key areas.  I am confident that the new Merck will have the right team in place to be able to deliver on the promise of this strong combination with Schering-Plough.”

The new Merck will have five primary divisions: Global Human Health; Animal Health; Consumer Health Care; Merck Research Laboratories; and Merck Manufacturing.  Each division and global support function leader will be a member of the new Merck Executive Committee and will report directly to Mr. Clark.

Global Human Health

Kenneth C. Frazier, currently executive vice president and president of Global Human Health (GHH), will lead the new GHH organization.

The new GHH organization will include the company’s prescription, vaccines and biologics businesses.  The combined GHH will have a broad portfolio of innovative in-line medicines and vaccines that, with the robust late-stage pipeline and an expanded global presence, will enable GHH to drive the combined company’s growth in markets around the world.

Raul E. Kohan

A new Emerging Markets group will be part of the new GHH organization and charged with focusing on regions and markets around the world that represent significant new growth opportunities. These include China; Asia Pacific; Latin America; and Middle East/Africa/Eastern Europe, including Russia and Turkey.

The leadership team for GHH, which will be the new company’s largest division, will include experienced executives from Merck and Schering-Plough.

Animal Health
Raul E. Kohan, currently senior vice president and president of Intervet Schering-Plough Animal Health, will lead the new Merck’s animal health business.  Mr.

Kohan will report to Mr. Clark and serve on the Executive Committee.

Schering-Plough’s Animal Health business is a world leader with market-leading products for a broad range of species and strong growth potential.  The division has more than 1,000 marketed products and generates approximately $3 billion in revenues from business operations in more than 140 countries.

Consumer Health Care
Stanley F. Barshay, currently chairman of Consumer Health Care at Schering-Plough, will lead this business for the new Merck on an interim basis while the company searches for a permanent leader.  Mr. Barshay will report to Mr. Clark and serve on the new Merck Executive Committee.

Mr. Clark said the new company plans to place an increased emphasis on growing the consumer business, particularly in markets outside the United States.  Schering-Plough’s Consumer Health Care business currently includes a number of iconic global brands such as Claritin, Coppertone and Dr. Scholl’s.

Stanley F. Barshay

Merck Research Laboratories
The new Merck Research Laboratories (MRL) will be led by Peter S. Kim, Ph.D., currently executive vice president and president of MRL.

The new structure for MRL is designed to foster innovation while instilling greater accountability at all stages of the R&D process through two core functions:  1) discovery and pre-clinical development, and, 2) clinical development and regulatory affairs.  In addition, a new central franchise structure focused on portfolio management will be aligned with the company’s Global Human Health division.  The new MRL will continue its focus on pursuing the best science around the globe through a Worldwide Licensing group.

Peter S. KIm

The combined research organization will have three new areas of dedicated focus — emerging markets, vaccines and biologics — to build on the significant investment that both Merck and Schering-Plough have made in this area.

Mr. Clark is taking a number of steps to ensure that the combined company will deliver on the science behind the merger.  Four of the top leaders from Schering-Plough Research Institute (SPRI) will hold leadership positions in the new MRL in senior preclinical, clinical and licensing roles. Most of the basic research heads for SPRI’s research sites will remain in their roles following the merger.  The new Merck is preparing for the broad integration of MRL and SPRI employees, and plans to maintain the continuity of key late stage development programs from Schering-Plough including, TRA (thrombin receptor antagonist), Simponi®, Saphris®, boceprevir, Bridion®, and IMPROVE-IT.

Merck Manufacturing
The new Merck Manufacturing division (MMD) will be led by Willie A. Deese, currently executive vice president and president of MMD.

MMD will create a strong, interdependent global supply chain fully focused on the needs of the combined company’s customers.  It will include new units for consumer health and animal health, and expanded technological capabilities for vaccines and biologics.

Global Support Functions
The new Merck Executive Committee will also include leaders of the following global support functions:  Mirian Graddick-Weir, executive vice president, Human Resources; Peter N. Kellogg, executive vice president and chief financial officer; Bruce N. Kuhlik, executive vice president and general counsel; and, J. Chris Scalet, executive vice president, Global Services and chief information officer.

Mr. Clark said that Richard S. Bowles III, Ph.D., currently senior vice president of Global Quality Operations at Schering-Plough, will serve as chief compliance officer at the new Merck.  Mr. Bowles will help ensure that the new Merck leads on ethics and compliance through central leadership and management of these activities.  He will report directly to Mr. Clark and serve on the Executive Committee.

As part of new Merck’s commitment to ensuring the well being of patients worldwide, the company will appoint a chief medical officer following an internal and external search of candidates.  This person will report directly to Mr. Clark and serve on the Executive Committee.

Smooth Integration
Integration teams from Merck and Schering-Plough are continuing to work together to ensure that following the completion of the merger the combined company is well equipped to begin its first day of business.  Adam Schechter will continue leading the integration effort for the new company, reporting to Mr. Clark in this role, and will also lead the combined company’s U.S. market.  Brent Saunders, who has been leading Schering-Plough’s integration team, also will continue to support the integration process following the merger’s close.

Mr. Clark said, “Our integration teams have been busy laying the groundwork for the combined company and, thanks to their hard work and dedication, our integration planning is proceeding smoothly and on schedule.”

Merck and Schering-Plough continue to expect the transaction to close in the fourth quarter of 2009.  Until that time, Merck and Schering-Plough will continue to operate as separate companies.

As previously announced, shareholders of both companies voted overwhelmingly to approve the proposed merger.  The transaction remains subject to the satisfaction of customary closing conditions and regulatory approvals, including expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, as well as clearance by the European Commission under the EC Merger Regulation and certain other foreign jurisdictions.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription, animal health and consumer health care products. Schering-Plough’s vision is to “Earn Trust, Every Day” with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.

Forward Looking Statement
This communication also includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the proposed merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s and Schering-Plough’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the proposed merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period, due to, among other things, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry; the ability to obtain governmental and self-regulatory organization approvals of the merger on the proposed terms and schedule; the actual terms of the financing required for the merger and/or the failure to obtain such financing; the failure of Schering-Plough or Merck stockholders to approve the merger; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; the possibility that the merger does not close, including, but not limited to, due to the failure to satisfy the closing conditions; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2008 Annual Report on Form 10-K, Current Report on Form 8-K filed on June 22, 2009, Merck’s other filings with the Securities and Exchange Commission (the “SEC”) available at the SEC’s Internet site (www.sec.gov).

By Michelle Fay Cortez

AstraZeneca Plc’s experimental clot- fighting drug Brilinta beat Sanofi-Aventis SA’s and Bristol- Myers Squibb Co.’s Plavix in a study that also positioned it to compete with a recently approved blood thinner.

Brilinta prevented 16 percent more heart attacks, strokes and deaths than standard therapy with Plavix, the second-best selling medicine in the world with almost $10 billion in annual revenue. Brilinta also unexpectedly reduced the overall risk of early death from any cause by 22 percent, analysts said.

Brilinta’s potency didn’t cause more episodes of serious bleeding, a common complication seen with drugs that ward off heart conditions by preventing blood clots from developing, the research showed. The findings position Brilinta to rival Plavix and Eli Lilly & Co. and Daiichi Sankyo Co.’s Efient for millions of patients suffering from heart attacks or severe chest pain.

“It’s clearly better than we anticipated,” Michael Leacock, an analyst at Royal Bank of Scotland in London, said in a telephone interview. “It certainly seems to be a more competitive product than we would have expected.”

About 1.3 million Americans are hospitalized each year with heart attacks and chest pain known as acute coronary syndromes. While aspirin and Plavix have lowered their subsequent health risks, cardiovascular disease remains the leading cause of death worldwide. Death from any cause was also significantly lower in patients taking Brilinta, according to the results of the study known as Plato.

‘New Standard’

“I think this will become the new standard of care,” said Douglas Weaver, a cardiologist at Henry Ford Hospital in Detroit and a past president of the American College of Cardiology, in an interview. “It’s more rapid, more effective and it appears to be safer” than Plavix and Efient. “I don’t think they could have done much better than they did in this trial,” he said.

The study included more than 18,000 patients in 43 countries. Those in North America may have done worse on Brilinta, a finding researchers couldn’t explain. That raised questions among analysts about future sales in the U.S.

“The North American market is such a big issue in terms of sales,” Leacock said in an interview. “This North American subgroup leaves a little more room for debate.”

Sales Estimates

AstraZeneca faces lower-priced competition on products that generate 62 percent of sales by 2014 and needs Brilinta to help offset the lost revenue. While analyst estimates are sure to rise for Brilinta’s sales, it might not be enough to make the company’s shares more attractive, Leacock said.

“The consensus is already at $1 billion a year,” he said. “Even if you add another $1 billion to AstraZeneca’s sales in 2013, I’m not sure it makes a large difference to the investment case for AstraZeneca.”

AstraZeneca shares rose 6.5 kronor to 334.5 kronor in Swedish trading. U.K. markets are closed today for a holiday. The stock has gained 1.2 percent this year, compared with a 2.1 percent increase in the 17-member Bloomberg Europe Pharmaceutical Index.

Sanofi, which is set to lose patent protection on Plavix in 2011, fell 85 cents, or 1.8 percent, to 47.32 euros in Paris. The shares have risen 6.1 percent. Japan’s Daiichi Sankyo fell 60 yen, or 2.9 percent, to 1,985 yen. Seamus Fernandez, a Leerink Swann analyst, said in a note to clients that he is reducing his Efient sales forecast by $40 million to $55 million this year and by $1.025 billion to $900 million in 2015.

The trial, funded by London-based AstraZeneca, was one of the most eagerly anticipated findings presented at the European Society of Cardiology meeting in Barcelona this week, researchers said. It was simultaneously published in the New England Journal of Medicine yesterday.

Plavix

“Bristol-Myers Squibb and Sanofi-Aventis have not had an opportunity to fully analyze the results of Plato,” Laura Hortas, a spokeswoman for New York-based Bristol-Myers, said yesterday in an e-mail. Plavix is approved for use in a broad group of patients with cardiovascular conditions, while the Brilinta trial focused only on patients who suffer from acute coronary syndromes including heart attacks and chest pain, Hortas said.

The U.K. drugmaker plans to file for approval of Brilinta in the fourth quarter in Europe and the U.S. and hopes to begin selling it next year, said Gunnar Olsson, AstraZeneca’s head of cardiovascular therapy.

Prevent Clumping

Brilinta, Plavix and Efient, which is sold as Effient in the U.S., all work by preventing platelets from clumping together in the blood to form clots. Plavix and Effient, which was approved this year in Europe and the U.S., last for the life of the platelet, or about a week, and are given once a day. Brilinta needs to be taken twice daily, and patients are likely to comply with that regimen, said David Snow, AstraZeneca’s vice president of cardiovascular global marketing.

“You’ve had a heart attack,” Snow said in an interview in Barcelona. “You’re certainly going to be motivated to avoid another one.”

About 30 percent of patients don’t respond well to Plavix. Brilinta’s effects wear off in a few days, making surgery easier for patients who need it.

One in 10 patients rushed to the hospital with chest pain or heart attacks actually need by-pass surgery, said Christopher Cannon, a cardiologist at Brigham and Women’s Hospital in Boston. If they are given Plavix or Efient, they must wait five days before getting the surgery, he said.

“It’s a huge conundrum, a headache for doctors, hospitals and patients,” he said in a telephone interview. “This opens the door. It’s a neat differentiating factor that could open up treatment options.”

Major Bleeding

In the study, 9.8 percent of patients taking Brilinta for a year after being treated for a heart attack or worsening chest pain suffered another heart attack or stroke, or died from vascular disease, compared with 11.7 percent of those given Plavix. Overall, 4.5 percent of Brilinta patients died from any cause, significantly fewer than the 5.9 percent of Plavix patients who died.

The rates of major bleeding were similar between the two groups, occurring in 11.6 percent of those on Brilinta and 11.2 percent of those on Plavix. Fatal bleeding in the brain was more frequent in those given Brilinta, while fatal bleeding in other areas was more common with Plavix. Brilinta was linked to more serious bleeding in the brain and stomach of patients who didn’t undergo bypass surgery, the study found.

“You have to keep the big picture,” said Jay Horrow, AstraZeneca’s executive director of clinical development. Brilinta had fewer patients with fatal bleeding overall than Plavix, he said.

To contact the reporter on this story: Michelle Fay Cortez in London at mcortez@bloomberg.net

Sandra E. Poole may have landed the toughest job in biotechnology: running Genzyme Corp.’s Allston Landing plant.

The Cambridge-based biotech giant has been struggling to overcome production problems at the plant that caused a summer shutdown and the temporary rationing of a pair of Genzyme’s key enzyme replacement drugs, Cerezyme and Fabrazyme. That makes Allston Landing ground zero for the company’s campaign to rebuild inventories of the drugs – and restore its reputation – in the face of mounting competition.

Last week, Poole, 45, hosted inspectors from the European Medicines Agency who wanted to see the improvements Genzyme had put in place to prevent a recurrence of the virus that forced the decontamination and sterilization of the plant. Poole marked the effort’s success by getting the sixth and last bioreactor up and running, shortly after 2:30 a.m. Friday, returning the plant to full production for the first time since the virus was discovered in June.

Next up: a return visit from Food and Drug Administration inspectors, who have been critical of Genzyme’s manufacturing operations over the past year and are eager to examine the new controls and procedures it has implemented over the summer.

“We know they’re coming back in the coming weeks or months, and we’re ready for that,’’ said Poole, who took over in early July as Genzyme’s senior vice president for biologics operations and site leader at the Allston Landing facility, which overlooks the Charles River.

The FDA inspection has yet to be scheduled, and officials at the regulatory agency are keeping mum on their likely timetable. “We don’t as a rule announce our inspections,’’ said FDA spokeswoman Karen Riley. But with the agency in recent weeks giving a pair of competitors, Shire and Protalix Biotherapeutics, approval to prescribe rival drugs more widely before they have won commercial approval, the stakes are high for Genzyme.

“I’m not sure they were as attentive to the problems at first as they could have been,’’ said Ira Loss, executive vice president at Washington Analysis, a research firm in Washington, D.C., that tracks regulatory issues. “The FDA wants to make sure somebody is responsible, that somebody is accountable for production there.’’

That somebody is Poole, who was born and raised in the Canadian province of Ontario and ran Genzyme’s production plant in Geel, Belgium, outside Brussels, for the past five years.

Poole had been scheduled to return this year to Cambridge, where she worked previously, in a corporate position in global affairs. But that plan changed after the FDA sent Genzyme a warning letter in February identifying deficiencies in its drug-producing equipment and processes that inspectors found at the Allston plant last fall.

Genzyme’s top executives decided to tap Poole to oversee operations at Allston Landing as well as a Framingham plant under construction. The new plant will also make Cerezyme and Fabrazyme, ensuring Genzyme has enough capacity to avoid rationing in the future.

Poole has quickly assembled a new management team. It includes new hires, managers from other Genzyme sites, and the woman she succeeded, Kathleen Retterson, who has taken a job as vice president of biologics and risk management.

Poole also is on a corporate steering committee that oversaw an investigation that determined the virus detected at the Allston plant was Vesivirus 2117, the same strain found twice in the past at Genzyme plants. In those cases, the company had enough inventory on hand to avoid rationing of its drugs.

Poole said her team at Genzyme has been busy all summer designing new tools for testing for the virus, scanning incoming raw materials, and segregating personnel and equipment in the cell culture prep area from other production areas of the plant. While it has ruled out many possibilities, the company still has not identified the root cause of the virus, and Poole said it’s not certain it ever will.

She said no effort will be spared to prevent another virus from contaminating the plant. “Do I feel like I’m under a magnifying glass?’’ she said. “I suppose. This is a vital effort for Genzyme. This is really being billed as a global program. We’re developing a remediation program that we’ll use at all our biologics plants.’’

Robert Weisman can be reached at weisman@globe.com.

By Kate Kelland

LONDON (Reuters) – A sensor made with gold nanoparticles can detect lung cancer in a patient’s breath and may offer a diagnosis before tumors show up on an x-ray, Israeli scientists said on Sunday.

The device, which the developers say would be cheap enough for everyday use by family doctors, detected lung cancer with 86 percent accuracy and may offer a way to screen for a disease not usually diagnosed until it has spread and is no longer curable.

Dr. Hossam Haick, senior lecturer in the Faculty of Chemical Engineering and the Russell Berrie Nanotechnology Institute

It uses sensors based on gold nanoparticles to detect specific compounds — volatile organic compounds (VOC) — that lung cancer patients have in high levels in exhaled breath.

Breath testing is already recognized as a way of linking specific VOCs in exhaled breath to a certain medical conditions. In 2006, researchers found dogs could be trained to smell cancer on the breath of patients with 99 percent accuracy.

Hossam Haick, one of the scientists working on the sensor, said he hoped it could soon allow doctors to have a simple test at hand to screen people during routine appointments.

“Conventional diagnostic methods for lung cancer are unsuitable for widespread screening because they are expensive and occasionally miss tumors,” Haick and colleagues wrote in Nature Nanotechnology.

“This device is not at all expensive. The whole idea in this development was to devise something very sensitive, and very cheap and very portable,” Haick, of the Technion-Israel Institute of Technology in Haifa, told Reuters.

Lung cancer kills 1.3 million people a year and is the leading cause of cancer death across the world. Only 15 percent of patients live more than 5 years, in part because the disease is usually diagnosed so late.

The device developed by Haick and his colleagues is a nine-sensor array consisting of gold nanoparticles combined with different organic groups that respond to various VOCs released by lung tumors.

They tested 56 healthy people and 40 patients who had been diagnosed with lung cancer using conventional methods.

They found the sensor could distinguish the breath of lung cancer patients from the of the control group with more than 86 percent accuracy.

Haick said the patented device needed to be more rigorously tested and obtain approval from drug licensing authorities before it could go into production.

“I would say that could take three to five years,” he said.

Various other methods exist to measure VOCs, including a breath test using color spots, but existing techniques are often expensive, slow and sometimes require the breath to be concentrated or dehumidified first.

(Editing by Louise Ireland)

Increased VC investment will benefit the industry, patients and Israel.

Kenneth Abramowitz

Venture capital plays a vital role in the future of the life science sector in particular, and Israel in general. VC finances 30% of all innovations in the drug and medical device sectors.

Kenneth Abramowitz

The truth is simple: without these funds and the management capabilities they hold, innovation in the medical sector will grind to a halt. On the other hand, given adequate resources, the venture capital community can contribute to innovation, for the good of the industry, patients and Israel.

The state of the sector is important and cannot be taken for granted. The industry suffers from a significant lack of investment following a fall of 50% in support in 2009. In order to deal with the problem, the Israeli government must be proactive and work with the universities, hospitals and health institutions as well as private investors.

I’d like to suggest five steps that it is worth the government taking during 2009 and 2010 to increase investment in venture capital.

1. Allocating resources to VC: The government should allocate resources to venture capital through the Chief Scientist of the Ministry of Industry, Trade and Labor and other authorities that are involved in early stage financing. $50 million should be allocated over 10 years. This sum would be divided among existing funds by a supervisory fund and a fund or two would participate in every category. In order to receive financing a fund must raise private capital of at least double the amount being offered by the government. Only funds that invest at least 25% of their capital in Israel would be eligible.

2. Raising funding of innovations at universities: The government should encourage the universities to raise their funding of innovative applied research. At the same time universities and hospitals should support investments in start-up companies through between 5-10% of their donation reserves.

3. Tax benefits for VC investors: Capital taxes should be cancelled on all money invested in funds that was raised from 2009-2011 and at least 25% of capital is invested in Israel.

4. Income tax must be reformed to make Israel more business friendly. The required change would raise income from taxes and attract capital and jobs to Israel. As part of the reform in taxation law pre-rulings should be discontinued and when a pre-ruling is necessary a solution must be provided within a month at most.

5. There should also be reform regarding clinical trials: This reform should include changes and improvement in the supervision process for clinical trials by government regulators and hospitals, and this would speed up approvals and the start of new trials without compromising hospital safety. Israel can learn from procedures in the UK and US.

Kenneth Abramowitz is a co-founder and managing general partner of NGN Capital

Published by Globes [online], Israel business news – www.globes-online.com – on September 1, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

The company has developed a cell-based chronic wound treatment, which is already used successfully in Israel.

Gali Weinreb

Biotechnology wound care treatment developer MacroCure Ltd. has raised $8 million at a company value of $53 million, after money, from investors, including private investors in the global pharmaceutical industry.

MacroCure raised $5 million in its previous financing round six months ago from Eli Hurvitz’s Pontifax Fund, the company’s largest shareholder. Pontifax and Zeev Bronfeld were behind the establishment of the company. Bronfeld is a cofounder of Protalix Biotherapeutics Inc. (AMEX:PLX) and is a major shareholder in D Medical Industries Ltd. (TASE:DMDC), Biomedix Incubator Ltd. (TASE:BMDX), and the Cleantech incubator of Altshuler Shaham Ltd. in Haifa.

MacroCure was established on the basis of a discovery that Sheba Medical Center Tel Hashomer sold a decade ago, but which was never commercialized. The product, CurexCell, a cell based therapy for chronic wounds to restore the wound healing process, is only available in Israel, where it has successfully treated 3,000 patients.

MacroCure hopes to use information from clinical trials to shorten regulatory procedures in other countries. Both the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) have decided that the company needs to conduct only one clinical trial to obtain marketing certification. The company has said that it wants to take CurexCell through the marketing stage and that it is not seeking a partner at this time.

MacroCure CEO Dr. Mitchell Shirvan was previously head of cell therapy at Teva Pharmaceutical Industries Ltd. (Nasdaq: TEVA; TASE: TEVA). MacroCure chairman David Ben-Ami was previously managing director of Boston Scientific Israel Ltd. and business development manager at Teva.

CurexCell is a cell suspension containing a white blood cell mixture taken from the residue of hemoglobin donations. Shirvan has called this mixture a “cocktail” of blood cells, which secrete enzymes that are responsible for natural wound healing in healthy people. The cells are taken from healthy donors, activated by a proprietary technique, and are subsequently applied locally to the chronic wound over a period of several months, resulting in significant improvement even in deep and large wounds.

Published by Globes [online], Israel business news – www.globes-online.com – on September 1, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

A growing number of companies are exploring molecules that modulate targets, rather than just switching them on or off.

By Megan Scudellari

The Scientist |Volume 23 | Issue 9 | Page 65

It started with an obsession. In 2002, Vincent Mutel began to talk about allosteric modulators, think about allosteric modulators, even dream about them. Few drug companies were pursuing allosteric modulators—small molecules that regulate a receptor or enzyme by binding to a site distinct from the target’s active (or orthosteric) site. Such ligands were widely recognized for their role in naturally regulating G protein–coupled receptors (GPCRs), many of which are known drug targets. But at the time, allosteric modulators and their signaling pathways had a reputation of being difficult to work with (they are), the molecules were believed to be insoluble (they are, in fact, soluble), and their efficacy was not proven (it soon would be). Still, Mutel had great hope.

Vincent Mutel

His newly formed company, Addex Pharmaceuticals, was struggling under its original business plan as a specialty pharma focused on addiction therapies, and Mutel realized the company needed to make a radical change. So he thought of a radical solution. While working at Roche a year earlier, Mutel participated in the discovery of the first positive allosteric modulator for a metabotropic glutamate receptor, mGluR1, one in a family of receptors intensively studied for their therapeutic potential in a wide range of neurological disorders, including Parkinson’s and schizophrenia. (The modulator is termed positive because it enhances the receptor’s activity.) The results convinced Mutel of the power of allosteric modulation. He spoke with the Addex staff, approached investors, and within a year, the company had shifted its business plan from a specialty pharma to a platform biotech exploring allosteric modulation. “Making allosteric modulation work became our mission on Earth,” says Mutel.

Addex was one of the earliest and most aggressive companies to pursue allosteric modulation, but it is certainly not the last. “There’s a good boatload of biotech companies going in the same direction,” says Maik Klasen, a biotech analyst at Frost & Sullivan. And major pharma companies are also jumping aboard: GlaxoSmithKline recently completed a phase I trial of a positive allosteric modulator to treat schizophrenia.

There are several proposed benefits to allosteric modulators. Orthosteric sites, the traditional targets of many drug discovery programs, are highly conserved among protein superfamilies, such as GPCRs and kinases, so it is difficult to specify drugs to subtypes of receptors. Allosteric binding sites, on the other hand, are quite selective. Functionally, allosteric modulators act by enhancing or inhibiting the binding and/or signaling of an orthosteric ligand, mimicking normal physiological rhythms because they have no effect unless an endogenous ligand is bound to the orthosteric site. Orthosteric agonists and antagonists act like light switches, turning receptors constitutively on or off independently of endogenous ligands, but allosteric modulators can function as dimmer switches, modulating a receptor’s activity in increments. Because they are quiescent when there is no ligand attached to the orthosteric site, research suggests that large doses of such molecules would not cause toxicity in the same way as high doses of an orthosteric ligand.

The anticipated flood of allosteric modulators to the market will take some time, as most are still in early clinical phases.

Now, the field awaits enough clinical data to prove that the proposed benefits will outweigh any unwanted side effects, such as regulation of other signaling pathways in a cell. Two commercially available allosteric modulators have raised hopes that this category of drugs will have market success, but without more clinical data, the platoon of advantages attributed to allosteric modulators still remains hypothetical, says Klasen. “In biological terms, it makes sense. But in clinical terms, we still have to see how these modulators work in the body.”

Slow and steady

In 2003, Addex began a massive effort to transform allosteric modulator discovery from a haphazard, luck-ridden process into an industrialized operation. “Coming from orthosteric development, this was a big challenge. At first, we were lost. We were shooting in the dark,” says Mutel. Classical functional assays are cumbersome when used to measure a dynamic change in a GPCR’s function rather than simply determining whether it’s on or off. What’s more, confirming that an allosteric modulator, a noncompetitive molecule, is binding to an expected target requires a great deal of cross-checking, says Mutel. “We had to think from scratch, almost had to rediscover the entire drug development process.”

Today, Addex boasts a library of over 70,000 allosteric modulators for receptors from all three GPCR families and a system of novel, proprietary assays for screening the molecules for clinical potential. The company currently has allosteric modulators against 18 targets in optimization, preclinical or clinical trials, partnerships with Merck and Johnson & Johnson, and recently expanded its platform to include non-GPCR targets. “Addex has had great success with their program,” says Klasen. “Their name comes up all the time.”

Yet two larger pharmaceutical companies beat Addex to the market: Amgen’s Sensipar (cinacalcet) for hyperparathyroidism, a positive modulator of the calcium-sensing receptor, was approved by the US Food and Drug Administration (FDA) in 2004, and Pfizer’s Selzentry (maraviroc) for HIV infection, a negative modulator of the chemokine receptor CCR5, hit the shelves 3 years later.

In 2006, a team of structural biologists and chemists at deCODE genetics pursued an allosteric modulator for a notoriously challenging drug target. Phosphodiesterases are a well-known target class in the pharmaceutical industry, a superfamily of enzymes that hydrolyze cAMP, taking an active part in signal transduction throughout the body. (Viagra, for example, is a PDE5 inhibitor.) But there are no compounds on the market for PDE4, which research suggests plays a role in chronic obstructive pulmonary disease, asthma, inflammation and cognition. Researchers have been unable to target the four unique isoforms of the enzyme because of their highly conserved active sites, says Lance Stewart, head of structural biology at deCODE.

To specifically target the fourth isoform of PDE4, PDE4D, implicated in inflammation and cognition, deCODE researchers took a structural approach. They solved the crystal structure of the enzyme, then identified a binding site for an allosteric ligand. (Compounds that target the PDE4 active site produce significant side effects, such as nausea and vomiting.) Using a real-time kinetic assay, the team assessed the effects of different molecules at the allosteric site and found DG071. The company recently received FDA clearance to begin phase I clinical testing of DG071 in Alzheimer’s and other cognitive diseases. A structure-based drug design project normally takes two and a half years, says Stewart, but DG071 took 3 years. “When you’re dealing with something complicated like modulation of allosteric sites, you have to do more heavy lifting,” he says.

“These are extremely difficult compounds to develop,” agrees John Krayacich, CEO of Marinus Pharmaceuticals, which is developing an allosteric modulator for the treatment of epilepsy. But large pharmaceutical companies need to rise to that challenge, say biotech experts. “Big pharma is already quite aware their old drug discovery engine is running out of targets,” says Klasen. “They have to go to the next level of complexity, and this includes allosteric drugs.”

Signing up

Krayacich, who last year joined Marinus from Novartis, believes that’s already occurring, estimating that more than half of big pharma’s drug discovery programs are now targeted at allosteric modulators. “My impression is there’s a lot of work going on,” says Ken Rubenstein, principal biotech consultant at Lion Consulting Group.

Early last year, Addex licensed ADX63365, a positive allosteric modulator for mGluR5 for the potential treatment of schizophrenia, to Merck, receiving $22 million upfront and a promise for $455 million in milestone payments for the first product in two indications and $225 million for each additional product in two indications, plus royalties. Such a large investment means Merck expects a big payback, says Klasen. “Merck obviously wants to make money on this drug, so they expect a few billion dollars in market potential.”

But that’s not to say the market is clamoring for just any allosteric modulator. In 2007, Evotec, a biotech devoted to small molecule therapeutics, completed phase II trials for EVT201, a partial positive allosteric modulator for the GABA-A receptor, licensed from Roche to treat insomnia. But despite positive efficacy results and a better safety profile than many insomnia drugs on the market, says John Kemp, chief R&D officer at Evotec, the company has been unable to find a partner to advance the drug, which would have to compete with such market giants as Ambien and Lunesta, to the expensive phase III trial.

If a biotech pursues indications in the big therapeutic areas, like the central nervous system, an allosteric drug will drum up a lot of excitement and financing, says Klasen. But an actual flood of allosteric modulators to the market will take some time, he warns, as most are still in early clinical phases. “I would not expect the market to explode before the next 7 to 9 years,” he says. “Most of these drugs aren’t yet ripe for primetime.”

By SHIRLEY S. WANG

If you’re one of those people whom mosquitoes tend to favor, maybe it’s because you aren’t sufficiently stressed-out.

Insects have very keen powers of smell that direct them to their targets. But for researchers trying to figure out what attracts or repels the pests, sorting through the 300 to 400 distinct chemical odors that the human body produces has proved daunting.

Now scientists at Rothamsted Research in the U.K. have been making headway at understanding why some people can end up with dozens of bites after a backyard barbecue, while others remain unscathed. The researchers have identified a handful of the body’s chemical odors—some of which may be related to stress—that are present in significantly larger concentrations in people that the bugs are happier to leave alone. If efforts to synthesize these particular chemicals are successful, the result could be an all-natural mosquito repellent that is more effective and safer than products currently available.

“Mosquitoes fly through an aerial soup of chemicals, but can home in on those that draw them to humans,” says James Logan, a researcher at Rothamsted, one of the world’s oldest agricultural-research institutions. But when the combination of human odors is wrong, he says, “the mosquito fails to recognize this signal as a potential blood meal.”

The phenomenon that some people are more prone to mosquito bites than others is well documented. In the 1990s, chemist Ulrich Bernier, now at the U.S. Department of Agriculture’s Agricultural Research Service, began looking for what he calls the “magic compounds” that attract mosquitoes. His research helped to show that mosquitoes are attracted to humans by blends of common chemicals such as carbon dioxide, released from the skin and by exhaling, and lactic acid, which is present on the skin, especially when we exercise. But none of the known attractant chemicals explained why mosquitoes preferred some people to others.

Rothamsted’s Dr. Logan says the answer isn’t to be found in attractant chemicals. He and colleagues observed that everyone produces chemicals that mosquitoes like, but those who are unattractive to mosquitoes produce more of certain chemicals that repel them.

Misguided Mosquitoes

“The repellents were what made the difference,” says Dr. Logan, who is interested in the study of how animals communicate using smell. These chemicals may cloud or mask the attractive chemicals, or may disable mosquitoes from being able to detect those attractive odors, he suggests.

Besides delivering annoying bites, mosquitoes cause hundreds of millions of cases of disease each year. As many as 500 million cases of malaria are contracted globally each year, and more than one million people die from it, according to the Centers for Disease Control and Prevention. Mosquitoes can also spread West Nile virus, dengue fever, yellow fever and other illnesses.

Currently the most effective repellents on the market often contain a chemical known as DEET, which has been associated in some studies with potential safety concerns, such as cancer and Gulf War syndrome. It also damages materials made of plastic. The federal Environmental Protection Agency has determined that DEET, when used as directed, is safe.

The Rothamsted team set out to get the mosquitoes’ viewpoint. The researchers separated human volunteers into two groups—those who were attractive to mosquitoes and those who weren’t. They then put each of the volunteers into body-size foil bags for two hours to collect their body odors. Using a machine known as a chromatograph, the scientists were able to separate the chemicals. They then tested each of them to see how the mosquitoes responded. By attaching microelectrodes to the insects’ antennae, the researchers could measure the electrical impulses that are generated when mosquitoes recognize a chemical.

Dr. Logan and his team have found only a small number of body chemicals—seven or eight—that were present in significantly different quantities between those people who were attractive to mosquitoes and those who weren’t. They then put their findings to the test. For this they used a so-called Y-tube olfactometer that allows mosquitoes to make a choice and fly toward or away from an individual’s hand. After applying the chemicals thought to be repellant on the hands of individuals known to be attractive, Dr. Logan found that the bugs either flew in the opposite direction or weren’t motivated by the person’s smell to fly at all.

The chemicals were then tested to determine their impact on actual biting behavior. Volunteers put their arms in a box containing mosquitoes, one arm coated with repellent chemicals and the other without, to see if the arm without the coating got bitten more.

Significant Repellency

The group’s latest paper, published in March in the Journal of Medical Entomology, identified two compounds with “significant repellency.” One of the compounds, 6-methyl-5-hepten-2-one, is a skin-derived compound that has the odor of toned-down nail-polish remover, according to George Preti, an organic chemist at the Monell Chemical Senses Center in Philadelphia, who is involved in a separate line of research into insect-biting behavior. The other, identified in the paper as geranylacetone, has a pleasant odor, though there is some question about whether the chemical is formed by the human biochemical process or is picked up in the environment, Dr. Preti says.

Dr. Logan declined to comment about the specific chemicals because of proprietary concerns. He says the findings have been patented and the group is working with a commercial company to develop the compounds into a usable insect repellent. One issue that still needs to be resolved: how to develop a formulation of the repellent chemicals that will stay on the skin, rather than quickly evaporating as they do naturally. The hope is to get a product to market within a year or two, he says.

Some of the chemicals researchers identified are believed to be related to stress, Dr. Logan says. Previous research has shown that these particular chemicals could be converted from certain other molecules and this could be as a result of oxidation in the body at times of stress, he says. However, it’s not clear if the chemicals observed by the Rothamsted researchers were created in this way, and research is continuing to answer this and other questions.

Dr. Logan suggests that mosquitoes may deem hosts that emit more of these chemicals to be diseased or injured and “not a good quality blood meal.” Proteins in the blood are necessary for female mosquitoes to produce fertile eggs, and Dr. Logan says it might be evolutionarily advantageous for mosquitoes to detect and avoid such people.

Other Research

Other research includes an effort by scientists at the University of California, Riverside, who published a paper in the journal Nature last week identifying a recently discovered class of molecules that inhibit fruit flies’ and mosquitoes’ ability to detect carbon dioxide. Mosquitoes can detect carbon dioxide emissions from long ranges, so turning off the ability to detect the gas, perhaps by releasing the inhibiting molecules into the environment, may be a way of keeping the bugs at bay, the researchers suggest. Another team, at the Monell Chemical Senses Center, is launching a study into whether the taste of human skin and blood are related to the insects’ interest in biting certain individuals.

Brainsway is currently conducting a number of clinical trials in parallel to test the effectiveness of Deep TMS for treating several diseases.

Adi Ben-Israel

Brainsway Ltd. (TASE:BRIN) has obtained EU CE Mark certification to market its Deep TMS (transcranial magnetic stimulation) for the treatment of depression. Deep TMS has been developed to treat a range of neurological disorders by non-invasive therapy.

In October 2008, Brainsway obtained CE Mark certification to market Deep TMS for the treatment of manic depression (bipolar disorder) in the EU following the success of a clinical trial for this indication.

Brainsway is currently conducting a number of clinical trials in parallel to test the effectiveness of Deep TMS for treating several diseases. In April, it announced a trial of the device to treat cocaine addition with the US National Institute on Drug Abuse, a unit of the National Institutes of Health.

Yesterday, the company announced preliminary good interim results for Deep TMS for the treatment of Parkinson’s disease conducted at Sheba Medical Center Tel Hashomer, in Israel.

Brainsway’s share rose 7% by mid-afternoon to NIS 10.90, giving a market cap of NIS 394.5 million.

Published by Globes [online], Israel business news – www.globes-online.com – on September 3, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

* Japanese will gain big Sepracor U.S. sales force

* Bid is friendly, with both boards approving

* Looking to promote experimental schizophrenia drug

* 2nd-biggest Japanese overseas acquisition this year

* Sepracor +26 pct before Nasdaq halt, Dainippon +1.2 pct (Adds Dainippon president comments)

By Toni Clarke and Yumiko Nishitani

BOSTON/TOKYO, Sept 3 (Reuters) – Dainippon Sumitomo Pharma Co Ltd agreed on Thursday to buy U.S. drugmaker Sepracor Inc for $2.6 billion, giving the Japanese firm a big, local sales force in the world’s largest drugs market.

The deal is the latest in a string of overseas acquisitions by Japanese drugmakers keen to grow outside a mature home market and build product pipelines before key drug patents expire.

Dainippon, Japan’s No.7 drugmaker by revenues, will gain a sales force of 1,200 familiar with central nervous disorders as it looks to promote its experimental schizophrenia drug lurasidone, which has performed well in late-stage trials.

It will also gain Sepracor’s insomnia drug Lunesta, asthma drug Xopenex and an experimental epilepsy drug.

“We anticipate our business will shrink if we focus only on Japan, where medical prices are under pressure,” Dainippon Sumitomo President Masayo Tada told a news conference.

“Even if the U.S. carries out healthcare reform it’s not as if the market is going to halve. It will remain the world’s biggest drug market.”

The deal is the fourth-largest overseas acquisition by a Japanese drugmaker, and the second-biggest this year by any Japanese company.

Dainippon’s shares climbed 1.2 percent in a weaker Tokyo market [.T], with volume at six times the daily average this year. Some analysts said the purchase was the easiest route into the U.S. market, others said it looked pricey and risky.

Dainippon will pay $23 cash for each share, a premium of 27.6 percent on Tuesday’s close before media reports of the deal sent Sepracor’s stock surging to $22.8 on Wednesday. The acquisition cost is roughly equal to Dainippon’s annual sales.

“It’s a very expensive deal for a company of Dainippon Sumitomo’s size and also very risky, given the series of patent expirations on Sepracor’s mainstay drugs in the next few years,” said Credit Suisse analyst Fumiyoshi Sakai.

“Dainippon must be extremely confident in lurasidone, although I have some doubts,” he said, adding the deal would not have been possible without the backing of the Sumitomo Group, which includes Sumitomo Mitsui Financial Group Japan’s third-biggest bank. Dainippon is majority-owned by Sumitomo Chemical.

Aaron Gal, an analyst at Sanford Bernstein, said that based on projections for 2013, the deal values Sepracor at 3.5 times sales, compared with 3.1 times for the average of other specialty pharmaceutical and generic drug industry acquisitions.

It also values Sepracor at 19.4 times EBITDA (earnings before interest, taxes, depreciation and amortisation) compared with an average of 15.1 times for other deals, he said.

“Arguably, Dainippon is buying a U.S. sales force it can leverage to promote its current and pipeline products,” said Gal.

“We are unconvinced that this is the most sensible option for the company given the alternatives of building a sales team internally or acquiring a higher-performing sales team at a more rational price.”

Dainippon said it would raise 200 billion yen ($2.17 billion) in bridge loans and use 50 billion yen in cash on hand for the acquisition.

NEW DRUG CLASS

Dainippon, which sells the hypertension drugs Amlodin and Prorenal, said last month that lurasidone worked significantly better than a placebo in a late-stage clinical trial. It will apply for U.S. approval next year and aims for launch in 2011.

The U.S. market for schizophrenia drugs is worth about 1.3 trillion yen a year, or 10 times the Japanese market, Dainippon’s Tada said.

With annual sales of 264 billion yen, Dainippon has been overshadowed by bigger rivals such as Takeda Pharmaceutical Co and Daiichi Sankyo Coboth of which have made large acquisitions to expand overseas.

Buying Sepracor will allow Dainippon to generate 40 percent of its sales outside Japan, which it now counts on for more than 90 percent of its business. At the same time, its research and development budget will increase by 45 percent to 80 billion yen.

Dainippon’s four mainstay products have patents that have either expired or will expire shortly. But its shares gained 21 percent in the year to Wednesday, bolstered by hopes that lurasidone will do well overseas.

Top-selling schizophrenia drugs such as AstraZeneca’s, Seroquel and Eli Lilly and Co’s , Zyprexa garner annual sales of around $4.5 billion. Other competitors include Johnson & Johnson’s Risperdal and Bristol-Myers Squibb’s Abilify.

Lurasidone belongs to a new generation of schizophrenia drugs known as atypical antipsychotics.

Rival products are Fanapt from Vanda Pharmaceuticals, Schering Plough’s Saphris and Serdolect from Danish pharmaceutical firm Lundbeck .

Sepracor has long been the subject of takeover speculation, and could face generic competition to Lunesta as early as 2012 if a generic drugmaker successfully challenges its patent, which expires in 2014. Xopenex is set to face generic competition in 2012.

Sepracor, based in Marlborough, Massachusetts, had 2008 sales of $1.3 billion.

Financial advisers to Dainippon Sumitomo were Nomura Securities and Thomas Weisel Partners LLC, while JP Morgan Securities Inc and Jeffries & Co advised Sepracor. ($1=92.30 Yen) (Additional reporting by Mayumi Negishi; Writing by Edwina Gibbs, Editing by Ian Geoghegan)

By RON WINSLOW

An experimental drug designed by Roche Holding AG’s Genentech unit against a new cancer target yielded encouraging results against two rare tumors, researchers said, potentially opening up a new front in the battle against the disease.

Charles M Rudin

In a small study, the drug, known as GDC-0449, shrank tumors in 18 of 33 patients, or 55%, with an advanced form of a skin cancer called basal cell carcinoma. In addition, the drug had a dramatic, though temporary, effect on a 26-year-old patient who had undergone multiple surgeries, chemotherapy and radiation in an unsuccessful battle against a brain cancer called medulloblastoma.

While the accounts involve just a handful of patients and the cancers are rare, researchers say the drug’s target, called the hedgehog pathway, is believed to be involved in other, more common and hard-to-treat tumors, including colon, pancreatic and ovarian cancers. Merck & Co. and Infinity Pharmaceuticals Inc., Cambridge, Mass., are among other companies developing drugs against the hedgehog pathway. The pathway is so named because geneticists who discovered the gene that is associated with the pathway noticed it had tiny hairs sticking out in multiple directions.

“This defines a new pathway that may have efficacy for multiple tumor types,” said Charles M. Rudin, associate director for clinical research at the Johns Hopkins Kimmel Cancer Center, and a co-author of two reports on the drug that are being published Thursday in the New England Journal of Medicine.

Genentech, which is collaborating with Curis Inc., Cambridge, Mass., in developing the drug, launched a 100-patient phase 2, or midstage, study early this year. Based in part on the encouraging results of the current trial, the company said it is hopeful that the Food and Drug Administration will consider approving the drug.

But success isn’t assured. “The studies are preliminary, and we don’t know in the long term how useful this class of drugs

Andrzej A. Dlugosz

will be,” said Andrzej A. Dlugosz, a researcher at the University of Michigan Comprehensive Cancer Center, Ann Arbor, and co-author of an editorial that accompanied publication of the findings. Still, he said, “hopes are big” that the responses seen in the trial hold promise for “this being a new approach” to cancer treatment.

Basal cell carcinoma is the most common skin cancer, affecting about one million Americans annually, but nearly all cases are easily cured with surgery. In very rare cases, the tumor spreads to surrounding tissue, or to other organs, where the prognosis for patients is poor. Medullablastoma is a form of brain tumor that typically afflicts children, but it is rare.

In about 90% of basal cell carcinoma cases and 30% of medullablastoma cases, the cancer is driven by a mutation in the hedgehog pathway.

The pathway plays a key role in prenatal development for several organ systems, but is apparently dormant in adults, a fact that may explain why there were few significant side effects in the study, researchers said. That would make the drug easier to use in combination with chemotherapy in cancers by avoiding an accumulation of side effects.

Getting a response in 55% of participants is unusual in an early stage cancer trial—especially since patients with a variety of tumors are typically enrolled. But researchers suspected, based on animal studies, that patients with basal cell carcinoma would be especially likely to benefit from the drug, and after the first enrolled patient had a significant response, they deliberately sought out more patients with the disease.

“This is a different paradigm for drug development,” Dr. Rudin said. By using knowledge of a tumor’s molecular mechanisms to help recruit patients, “we can move more quickly and focus our research more on patients who are likely to benefit from therapy,” he said.

The patient with medulloblastoma was diagnosed at age 22 and had exhausted all treatment options when he was enrolled in the study in April 2008. He was thin, in constant pain, required frequent blood transfusions, and tumors had spread throughout his body, some of which could be felt though his skin. Within two months of beginning therapy, his pain was gone, he was exercising on a bicycle and tumors were no longer palpable. “It was a pretty striking case,” Dr. Rudin said.

But within three months, examination indicated the cancer had developed resistance to the treatment and was progressing again. He died in September.

A analysis of his case, being published Thursday in the journal Science, showed the very target of GDC-0449 in the hedgehog pathway developed resistance and rendered the drug ineffective. Frederic de Sauvage, vice president of molecular biology at Genentech who has been working on the pathway and developing the drug since the mid-1990s, said that finding was additional proof that they had hit the correct target. It also suggests that a better time to use the drug is before a patient is subjected to a variety of other treatments that could cause the target to develop mutations that become resistant to treatment.

Write to Ron Winslow at ron.winslow@wsj.com

* Clinical CROs in China to grow 18 pct annually

* Late-stage CRO revenue to reach $240 mln by 2012

* Lower costs, skilled workforce draw business

By I-Ching Ng

NEW YORK, Sept 3 (Reuters) – Companies that conduct research for drugmakers are poised for torrid growth in China as their multinational clients look to sell more medicines in the world’s most populous country and cut development costs.

Such contract research organizations, or CROs, charge large drugmakers for conducting all stages of research — from discovery of compounds that might be used as drugs, to animal studies and expensive clinical trials involving hundreds or thousands of patients with various ailments.

Most of the world’s largest drugmakers, including Pfizer Inc, Merck & Co and Novartis AG, have turned to local Chinese drug contractors with niche specialties and a cheaper pool of scientists to deliver less costly drug trials, and to gain access to China’s large pool of patients.

Total revenue of China’s CROs is unclear since the local drug contractors are dominated by scores of private businesses and only one publicly traded company, WuXi PharmaTech.

But CROs in China that specialize in late stages of including clinical trials, are on a fast-growth track, said Ranjith Gopinathan, senior research analyst at consulting firm Frost & Sullivan. They capture annual revenue of about $145 million, or less than 2 percent of the global CRO market. They are expected to expand at 18 percent annually, reaching $240 million by 2012, Gopinathan said.

Hence, multinational CROs, including U.S.-based Covance Inc and Charles River Laboratories International Inc.,  are aiming to be far bigger players in the country.

“The big drivers are the big, untapped and rapidly growing markets,” William Blair & Co analyst John Kreger said. “That’s what the pharma industry desperately needs right now.”

While the business in China thrives, Kreger said he expects growth of the global CRO market to dip into single-digit range in coming years because Western drugmakers are cutting back on how much they are willing to pay contract research companies.

China, India and other emerging markets are expected to help offset tepid CRO growth in other parts of the world.

China’s CROs largely came into being after the country joined the World Trade Organization in 2001 and developed a drug regulatory system under China’s State Drug Administration.

The increasingly competitive sector has at least 138 CROs, according to Shanghai-based consultant firm Modular R & D.

“(The) CRO industry in China as a whole is still young and fragmented, but they anticipate a quick ramp up toward standardization and global competitiveness,” said Mandy Chui, global leader for emerging markets at IMS Health , a U.S.-based consultancy that tracks market data on the pharmaceutical and healthcare industries.

BEYOND CHEMISTRY TO TOXICOLOGY

Over the years, Chinese CROs have focused on relatively inexpensive areas such as biology and chemistry — including screenings of chemicals to identify combinations with potential as medicines. They have also worked on manufacturing active pharmaceutical ingredients for generic drugs.

Experts said an increasing number of CROs in China, local and foreign-based, are moving into more lucrative stages of the drug development chain. They include preclinical studies, such as toxicology and other animal as well as human studies.

James Foster, chief executive of Charles River, estimates toxicology demand will surge “significantly” in 2010. “We would anticipate all the businesses we do in the U.S. and Europe we will eventually do in China,” Foster said in an interview. His company built a new preclinical facility in Shanghai in January and is planning to build a second site in China.

China’s annual market for toxicology — studies that typically use animals and are designed to root out serious side effects of drugs early in the game — is worth about $20 million. But it may jump to $200 million in five to seven years, said Joe Herring, chief executive of Covance. Covance’s CRO business in China should be profitable this year, with revenue doubling in 2010, he said.

With an abundant supply of primates, and less animal-rights advocacy, China has become a favorable destination for animal testing, said Frank Zhang, chief executive of GenScript, a biology CRO with operations in the United States and China.

To sell existing drugs to China, multinational drugmakers are required to conduct additional testing to obtain local approvals. Ronny Krishana, senior director of strategy and business development at Pfizer, said his company plans to collaborate with more than 500 hospitals and 2,000 doctors on at least 135 local clinical trial programs in 2010.

“Our investment in local clinical trials in China has increased dramatically in recent years,” Krishana said.

Despite the growth potential, Frost & Sullivan’s Gopinathan warned that concern over intellectual property, a limited number of qualified research sites and long approval processes for clinical trials would hold back China’s CRO market.

Still, the CROs are moving drug development in China into a more sophisticated and possibly more lucrative stage.

“China’s drug development industry can help the country build a new brand that is known for innovation and quality, so that ‘made in China’ will no longer be synonymous with manufacturing cheap products,” said Charles Huang, an executive with Sundia MediTec Company, a Shanghai-based CRO. (Editing by Steve Orlofsky)

GEN News Highlights

Roche is paying PTC Therapeutics $12 million up front as part of an agreement to develop small molecule CNS disease drugs. PTC separately announced that Celgene exercised its option to collaborate with the company on the development of GEMS-based candidates against an oncology target. The original agreement was inked in 2007, and Celgene made a $20 million investment in the company.

Under the terms of the collaboration and licensing deal with Roche, PTC will use its GEMS (gene expression modulation by small molecule) technology, and Roche will cover research costs. The aim initially is to develop orally bioavailable  candidates against four, jointly selected CNS disease targets. PTC says that it could earn up to $239 million in research, development, regulatory, and commercialization milestones per target plus double-digit sales royalties. Roche also has an option to add four additional targets to the collaboration across different therapeutic areas.

PTC’s GEMS technology is designed to identify small molecules that modulate post-transcriptional control mechanisms. The company says that candidates target processes that act through untranslated regions of mRNA.  Lead in-house candidate include the small-molecule VEGF inhibitor, PTC299, and ataluren (PTC124), which is in development for the treatment of nonsense mutation genetic disorders.

Ataluren is currently undergoing a pivotal clinical trial in patients with nonsense mutation Duchenne and Becker muscular dystrophy. PTC said it also aims to start a second pivotal trial of ataluren in patients with nonsense mutation cystic fibrosis during 2009. The company has an exclusive collaboration with Genzyme (www .genzyme.com) for the development and commercialization of ataluren outside North America.

The FDA and the European Commission previously granted the drug orphan drug status for the treatment of DMD and cystic fibrosis due to nonsense mutations. The FDA has also granted ataluren subpart E designation for expedited development, evaluation, and marketing.

In July, PTC started a Phase II trial assessing PTC299 in adult patients with neurofibromatosis type 2 (NF2). The drug is also undergoing a Phase 1b study in advanced solid tumors and a Phase Ib/II trial in metastatic breast cancer.

by Jean-Louis Santini Jean-louis Santini

WASHINGTON (AFP) – Researchers have found a gene that when blocked can keep mice from becoming obese, even if they consume a high-fat diet, new research released Thursday found.

AFP/File – Lab mice. Researchers have found a gene that when blocked can keep mice from becoming obese, even if …

The gene, dubbed IKKE, acts as the main control center for obesity in the lab animals. When it is successfully blocked, mice remain thin even if they are devouring high-fat foods, said Alan Saltiel, director of the University of Michigan’s Life Science Institute.

If further research shows IKKE is tied to obesity in humans, the gene and the protein it makes will be key targets for developing drugs to treat obesity, diabetes and related complications, he added.

“We’ve studied other genes associated with obesity — we call them ‘obesogenes’ — but this is the first one we’ve found that, when deleted, stops the animal from gaining weight,” said Saltiel, lead author of the paper appearing in the September 4 edition of the journal Cell.

“The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising,” he said.

Some of the mice ate a diet in which 45 percent of the calories were from fat.

Another group ate regular chow with 4.5 percent fat content.

They started the diets at eight weeks and continued through 14 to 16 weeks of age.

The gene IKKE produces a protein kinase, which also is called IKKE. Protein kinases are enzymes that effectively “turn on or off” other proteins. The IKKE protein kinase appears to target proteins which, in turn, control genes that regulate mouse metabolism.

When normal mice were on the high-fat diet, IKKE protein-kinase levels rose, the metabolic rate slowed, and the animals gained weight. Here the IKKE protein kinase acts as a brake on the metabolism, researchers said.

Meanwhile, mice on the high-fat diet did not gain weight, “apparently because deleting the IKKE gene releases the metabolic brake, allowing it to speed up and burn more calories, instead of storing those calories as fat,” they added in a statement.

Saltiel’s team is now searching for small molecules that block IKKE protein-kinase activity. IKKE inhibitors could become candidates for drug development, they said.

“If you find an inhibitor of this protein kinase, you should be able to obtain the same effect as knocking out the gene. And that’s the goal,” Saltiel said.

New treatments for obesity and diabetes — if successful candidates are identified and drug development carried out — may be a decade down the line, he said.

By Alice Park

Back in 1999, two researchers at the National Cancer Institute (NCI) received a long-awaited green light to launch separate studies on cancer care. Six months apart, Dr. Douglas Schwartzentruber and Dr. Larry Kwak began enrolling subjects to test an entirely novel weapon in the war on cancer — one they hoped would bypass the toxic effects of chemotherapy and give patients a new edge in halting the spread of tumors.

Vaccines enlist the immune system in the battle against cancer. Treatments would begin after surgery and chemo, to prevent relapse.

Both had the blessings of Dr. Richard Klausner, then NCI director. But even Klausner, a well-respected researcher, had to be persuaded at first. “I came to the NCI being quite skeptical about it,” he says of the new strategy.

And he wasn’t the only one. What Schwartzentruber and Kwak were hoping to do was prove they could vaccinate a patient against cancer — educate a body to, in essence, recognize and round up tumor cells the same way it polices viruses and bacteria. It certainly made good biological sense: the immune system is the body’s built-in defense mechanism, after all, so why not turn it against one of the most ornery diseases around?

The problem, of course, is that a tumor is not exactly a pathogen. What it is, at its core, is a collection of aggressively growing cells that can’t stop dividing. It is not entirely foreign, as a virus is; it does not infect healthy cells, as bacteria and viruses do. Turning the immune system against cancer cells would involve turning the body’s defense mechanisms against a part of itself. Designing a vaccine to do this entails creating the biological version of a stealth weapon encased in a smart bomb equipped with a guided missile.

And that was proving to be a bit too challenging. Nothing that hundreds of researchers in hundreds of trials had attempted had worked. While the vaccine idea made logical sense, the immune system, it seemed, just wasn’t designed to battle cancer this way.

But in June, after nearly a decade of carefully inoculating patients suffering from either advanced melanoma or a type of lymphoma, both Schwartzentruber and Kwak announced positive outcomes of their trials, at the American Society of Clinical Oncology meeting in Orlando, Fla. Their results, along with those of a trial vaccine against prostate cancer and an early candidate against a type of brain cancer, suggest that we might finally be on the way to unleashing the immune system against the disease.

It’s about time. Senator Edward Kennedy’s death after a yearlong battle with brain cancer is only the most prominent reminder that while many current treatments are certainly effective, they can be made even better. Though malignancies are now being caught earlier than ever before and treatments that target and control the disease are more effective than ever before, cancer is still the second biggest killer in the U.S., claiming more than half a million lives each year. Surgery, chemotherapy and radiation can do only so much when tumor cells hide in plain sight and even a single overlooked cell can seed new disease.

That’s where a vaccine-based strategy could make a difference. An immune system trained to recognize the first signs of new or recurrent growth can begin to attack malignancies far earlier than the best scans can detect them. And the latest vaccines incorporate clever new insights into how malignant cells can be tagged, exposed and destroyed. “Understanding how the immune system works is going to play a significant role in our treatment of cancer going forward,” says Dr. Len Lichtenfeld of the American Cancer Society.

It’s not just the biology that is getting better. Researchers are even fine-tuning when to give a cancer vaccine. The latest data from the lymphoma trial, for example, suggest that in some cases, the best time to train the immune system might be during a remission, when the body’s defensive cells are at their strongest. “It’s been a slow evolution, but we are seeing the first inklings that cancer vaccines can work,” says Dr. Steven Rosenberg, chief of the surgery branch at NCI and a cancer-vaccine pioneer who trained Schwartzentruber and Kwak.

When Is a Vaccine Not a Vaccine?

There may be no better example of what is meant by preventive medicine than the strategy of vaccination. A healthy person is given a tiny taste of a virus — flu or polio, say — that’s too weak to cause illness but just enough to introduce the body to the pathogen. If the virus later shows up for real, the immune system is primed and waiting for it.

That’s close to how a cancer vaccine works, but not precisely. Most experts see cancer vaccines as a hybrid of treatment and prevention. While it’s true that the Food and Drug Administration has approved vaccines against cervical and liver cancer, both are actually designed to fight the viruses most responsible for causing the disease, as opposed to targeting cancer itself — human papillomavirus in the case of cervical cancer and hepatitis B in the case of liver tumors.

Using vaccines to prevent nonviral cancers in someone who is disease-free is a whole different matter. For one thing, it’s much more difficult to determine a person’s chance of developing a particular type of cancer than it is to determine the likelihood of being exposed to, say, the influenza virus or chicken pox. What passes for “exposure” in the case of nonviral cancers is a combination of genes and environment and a range of other X factors that can vary from person to person. How do you vaccinate against your family legacy of breast cancer or your constant exposure to secondhand cigarette smoke?

But that doesn’t mean the immune system can’t be exploited in a different way. Cancer vaccines would ideally be used in patients whose disease has already been diagnosed and treated with surgery, chemotherapy or radiation. They would then be immunized as a way to prevent the cancer from coming back and spreading. Such metastases are actually the leading cause of death from cancer. “The charm of working with the immune system is that we can use the body’s own defense mechanisms to possibly get to that last cancer cell or at least create a surveillance system that keeps that cancer under control,” says Lichtenfeld.

Trial by Failure

Before they can seek out these smaller, hidden deposits of tumors, however, cancer vaccines must prove that they can actually target and shrink a cancer’s more conspicuous growths. This, it turns out, is obvious in theory but devilishly challenging to show in reality.

Take melanoma. In 2002 scientists at the John Wayne Cancer Institute in Santa Monica, Calif., thought they had finally figured out a way to turn the immune system against the skin cancer. Instead of trying to activate immune cells with snippets of tumor proteins they had created in the lab, they decided to grind up melanoma tumors and use the malignant slurry to prod the right immune cells into action. The result was Canvaxin, a vaccine against aggressive melanoma that was loaded up with 20 different tumor-specific components of melanoma, teaching the body new ways to recognize the disease. More than 1,500 patients were given the vaccine after being treated with surgery and chemotherapy. In the first five years of follow-up, the shot proved safe and worthy of moving into the most advanced level of human testing. But in April 2005, the scientists and the biotech company they had enlisted to develop the vaccine were forced to stop their studies when it became obvious that the vaccinated patients were not living any longer than the unvaccinated ones. “That put a damper on things,” says Schwartzentruber. “They had what they thought was a promising start, and it was an international, multi-institutional study with a large number of patients.”

In retrospect, Schwartzentruber says, the problem may have been that the vaccine was forced to work alone. Even the most well-sensitized immune system may be fooled by the homegrown nature of cancer, recognizing malignant cells as just another part of the body — which they are — and thus giving them a pass. When the cancer finally grows big enough to represent a real threat, it’s too late.

Schwartzentruber thinks he has a way around that problem. In some trials, after giving his vaccine to patients with advanced melanoma that has spread to other tissues, he adds an immune stimulator called interleukin-2 (IL2) for reinforcement. Alone, the vaccine would not cause any tumors to shrink. The IL2 treatment itself wasn’t very effective either; it shrank tumors in only 10% of patients. But combining the vaccine and IL2 has caused tumors in 22% of patients to regress — a doubling of effectiveness. “This teaches us a lesson: that combinations of biologic treatments are more powerful than their individual components,” says Schwartzentruber.

Kwak and his collaborators, led by Dr. Stephen Schuster at the University of Pennsylvania, see a similar power in pairing. Their vaccine, against a form of non-Hodgkin’s lymphoma known as follicular lymphoma, takes a slightly different, more personalized approach. Rather than relying on a commonly found antigen or snippet of cancer protein to teach the body to recognize the malignancy, they designed each vaccine using individual patients’ specific lymphoma profiles. They then partnered this customized concoction with another immune stimulator, GMCSF. Patients receiving the combination remained in remission on average 44 months after the vaccination, a 47% improvement in disease-free survival compared with those getting the uncustomized vaccine, who stayed in remission for just 30 months.

This study is also the one that yielded the most evidence that the best time to inoculate patients is when they’re in remission from their disease. While Schwartzentruber elected to administer his melanoma vaccine when his subjects were in the most advanced stages of illness, Kwak and his colleagues decided to capture the immune system at its best. They waited until the patients had been in remission for six months after chemotherapy, which rid the body of the bulk of the tumor burden. Give the immune system a break from that life-or-death battle, and it might be better able to do the surveillance work of corralling stray cells that escape the initial treatment. “I envision that vaccine approaches like this could be useful as maintenance therapy,” says Kwak. “We would use chemotherapy and surgery to debulk the tumor and then vaccinate to maintain remission.”

The Riddle of Success

Another way to make a vaccine more effective might be to manipulate the very nature of the tumor, so that it is a more obvious target for the immune system — a little like tying a more colorful fly on a fishing hook. The idea, says Dr. Patrick Hwu, chair of melanoma oncology at the University of Texas’ M.D. Anderson Cancer Center and a member of Schwartzentruber’s team, is to “get the tumor itself to look like a virally infected site, to get the whole immune system going.”

The untreated immune system is not helpless in all of this. Rosenberg has biopsied tumors and extracted immune cells called lymphocytes from patients with advanced cancer and has grown these cells in culture. In a test tube, the lymphocytes are perfectly capable of killing tumor cells. But in the body, for some reason, they can’t seem to stop a lesion from growing. So for melanoma, some researchers are working with a cream that can increase a tumor’s “foreignness” to the immune system, tagging it to look more like an unwelcome virus and less like a familiar self cell. Other groups are testing ways to shut off the immune suppressors that the tumor sends out to hinder the natural seek-and-destroy tendencies of the immune system. That makes sense. Supercharging the immune system while the immune suppressors are still at work is a little like revving a car engine without releasing the emergency brake: in both cases, you’re not going anywhere. And yet most early vaccine efforts have involved stepping on the gas alone.

One other way to get the immune system moving might be, in effect, to replace it with an entirely new one, says Rosenberg. If a vaccine can marshal the body’s defenses to recognize and destroy a tumor, could you rebuild those defenses from the ground up and this time design them so they’ll be especially good at fighting cancer cells?

Rosenberg’s thinking is based on the now familiar strategy of the bone-marrow transplant for leukemia and lymphoma, which are blood- and immune-cell cancers. Radiation is used to obliterate a patient’s cancer-tainted immune cells; those cells are then replaced by a population of new ones harvested from a healthy donor or grown from some of the patient’s healthy cells. Rosenberg refines this method for melanoma by first exposing immune-system cells to tumor cells in a dish, thus “training” them to sprout proteins that target cancer cells, and only then infusing them into patients. Already he has shown that such a fortified mix can cause tumor regression in up to 70% of melanoma patients.

Even that, Rosenberg says, can be improved on. He is tipping the odds further in favor of the anticancer cells by genetically modifying the tumor-fighting T cells so that cancer cells aren’t simply among the ones they recognize but are the only ones they recognize — eliminating the distraction of other infections and allowing the T cells to devote all their energy to the malignancy alone. In June he published results showing that such manipulation can cause regression of tumors in one-third of subjects. “I think the most important progress in using the immune system is not by a vaccine but by using cell-transfer approaches,” says Rosenberg. “Those are looking to be far more effective.”

Measuring that effectiveness will be another challenge. The melanoma- and lymphoma-vaccine studies both tracked only the extent to which tumors regressed and were not designed to document what most cancer experts — not to mention patients — see as the gold standard of any new therapy: survival. Do patients who are vaccinated live longer than those who are not? How do the vaccine’s cancer-controlling powers compare with those of the expanding list of drugs designed to sneak in and halt growing lesions by shutting off their supply of nutrients and oxygen or hampering their growth spurts?

Solving those riddles might be the most formidable challenge yet for the vaccine field. Some experts are already questioning the need for the lymphoma vaccine when a drug, rituximab, exists to control the disease. Kwak points out, however, that in addition to being able to seek out small deposits of tumor cells that even the best-targeted drug therapies might miss, vaccines are generally less toxic. Rituximab, for instance, can lead to viral infections and heart problems and may be toxic to the kidneys. If, as some researchers hope, cancer is ever to become more of a chronic disease like diabetes, which can be managed for life, finding treatments that are safe and effective over many years becomes critical. “The risk-benefit ratio begins to swing more against chemotherapy or targeted agents for long-term maintenance,” says Kwak. “Whereas a vaccine, with a favorable safety profile, is ideal for that kind of setting.”

If that’s true, then this first group of cancer vaccines is well on its way to seeding an entirely new field of immune-based treatments for cancer. “In some way, shape or form, our body repairs cancer cells and ‘prevents’ cancer,” says Lichtenfeld. “If it didn’t, we would have much more cancer than we actually see. How simple it would be for us to take some markers on a cancer cell’s surface and create a vaccine to help the body do what it’s supposed to do.” It’s not simple at all, as it turns out, but it’s an idea whose power and potential certainly make it worth the effort.

Although Financing Levels Are Starting to Increase, Biotech Still Needs to Be Savvy

Sumantha R. Sedor

For decades the biotech industry has provided lifesaving cures to the world, but now many biotech companies are in need of a lifesaving cure themselves—in the form of cash.

Analysts estimate that nearly half of public and private biotech companies have insufficient cash to subsist for even a year. Given the current economic crisis, which includes a tight credit market, an IPO drought, and investor reluctance, raising capital has become increasingly daunting, so much so that companies have been turning to other capital-raising structures that are customarily underutilized. In particular, biotech companies have been forced to engage in creative cash structures or alternative exit strategies in order to bring their products to market.

All hope should not be considered lost for biotech companies just yet, however. According to the second quarter 2009 MoneyTree Report, investments in the life sciences sector (biotech and medical devices industries combined) represented the highest percentage of total venture capital investments since 1995 and increased 47% to $1.5 billion from the previous quarter.

The same report notes that, similar to previous quarters, the biotech industry received the largest amount of funding for all industries in the quarter, and that funding increased 54% to $888 million from the previous quarter. Further, following positive Phase III trial results for its obesity drug, Orexigen Therapeutics completed a secondary stock offering that raised approximately $71 million in late July. In early August, following optimistic results for its investigational treatment for lupus, Human Genome Sciences raised almost $358 million, which is one of the largest biotech offerings so far this year.

But that doesn’t mean that biotech companies should start dusting off their precedent financing documents with visions of capital funds dancing in their heads. Although financing levels are starting to increase, the levels are still considerably lower than earlier in the decade and finding investors will still be laborious.  Additionally, such financings may only be short-term fixes. Fortunately, there are alternate, nondilutive options that biotech companies can implement to raise money and develop their pipelines such as strategic partnering, acquisitions, and royalty monetization that can result in long-term solutions.

Strategic partnering, either in the form of a license or through a strategic alliance, for a start-up or early-stage biotech company may be the key to its survival. Licensing allows a biotech company to grant a right in its intellectual property to another company in exchange for up-front payments, milestone payments, and/or royalties based on product sales.

The license can be tailored to be narrow in scope so that it only includes rights to certain territories, technologies, fields of use, dosage forms, indications, etc. This could allow, for example, a biotech company patent holder to license only a portion of its technology to raise cash for development and commercialization while keeping another part of the technology for itself. On the other hand, strategic alliances allow a biotech company to partner with another company to accomplish a mutual goal while dividing up the respective rights and obligations of the parties within that relationship.

Partnering with a seasoned pharmaceutical company or even a larger biotech company can provide a start-up or early-stage biotech company the expertise, leadership, commitment, and most importantly, the funds to allow for proper product development given the pharmaceutical company’s (or larger biotech company’s) aptitude and operational capability in the development and commercialization of new products.

Such a collaboration is equally beneficial for the partner as its patents expire or pipeline productivity fails to meet expectations; big pharma and larger biotech companies can turn to start-up or early-stage biotech companies to bolster their pipelines and diversify market penetration while mitigating risks. In fact, partners often view biotech companies as cost-effective incubators for new product pipelines.

Strategic partnering, however, isn’t just for start-up or early-stage biotech companies. At the end of July, Amgen and GlaxoSmithKline (GSK) entered into a major partnering relationship to commercialize denosumab, Amgen’s product for the treatment of postmenopausal osteoporosis. GSK will pay initial and near-term commercial milestones to Amgen totaling $120 million to share profits in Europe, Australia, New Zealand, and Mexico and to register, commercialize, and sell the drug in countries where Amgen has no presence, such as China, Brazil, India, Taiwan, and South Korea.

Perhaps one of the most widely known partnering relationships, and often touted as the most commendable, innovative, and successful, was formed in 1990 between Genentech and Roche.

The partnership was credited for uniquely solving a biotech company’s need for financing while strengthening a big pharma’s pipeline. During the relationship, Roche held a majority 55.9% stake in Genentech while Genentech remained independent to develop its oncology treatments. Over time, however, Roche became more and more reliant on Genentech’s pipeline and made an offer in July 2008 for the remainder of Genentech’s outstanding shares. Roche acquired Genentech in March 2009 for $46.8 billion.

Strategic alliances or licensing can occasionally trigger an acquisition, as it did for Genentech/Roche. And due to the recent economic climate, pharmaceutical companies may be predisposed to shift directly to acquisitions rather than entering into strategic partnering relationships while their pipelines dissipate and many small biotech companies fight off insolvency and sinking valuations.

Acquisitions by pharmaceutical or large biotech companies represent an alternate exit option for biotech companies to IPOs. The first half of 2009 has seen a wave of acquisitions by pharmaceutical companies, although not all acquisitions have been such goliath mergers as the Merck/Schering-Plough and Pfizer/Wyeth mergers. Instead, some recent acquisitions were the result of pharmaceutical companies paying a premium for less-established biotech companies, such as big pharma Johnson & Johnson’s (J&J) acquisition of biotech company Cougar Biotechnology for approximately $894 million.

Another alternative approach to raising capital is by royalty monetization, which is the sale of future revenue in the form of either royalties or product revenues. This is similar to partnering, as an investor has a shared goal for the success of the product underlying the revenue stream. Royalty monetization has been more popular in recent years, but is frequently limited to those biotech companies that already have (or expect very soon to have) a commercialized product or are already receiving some type of return on their intellectual property, such as from license agreements. There are some firms that specialize in royalty monetization such as Paul Capital Healthcare, Drug Royalty, and Royalty Pharma.

Although risks are associated with any of the aforementioned capital-raising alternatives, much can be mitigated by careful negotiating and drafting. Each biotech company has its own unique set of circumstances surrounding its capital-raising endeavors. Before seeking another round of financing, biotech companies should explore which options best meet their needs and can provide the lifesaving cash injection that the current economic climate especially demands.

Experience and Infrastructure Also Seen as Key Drivers in Region’s Ascent

Gail Dutton,  Genetic Engineering and Biotechnology News,  Sep 1 2009 (Vol. 29, No. 15)

The conversation about outsourcing to Asia has changed from cost reduction to opportunity. The recent BIOCOM “CalAsia Conference” in San Diego focused on strategies biotech companies can use to leverage the strengths of Asian biotech opportunities. Presenters agreed that Asia is becoming increasingly innovative as it gains experience and an infrastructure to support the biotech industry. Consequently, the work performed in Asia is moving up the value chain.

Hong Kong Science Park recently completed a biotech center with over 200,000 sq. ft. of laboratory space.

Steven Burrill, CEO of Burrill & Company, suggested that Asian nation’s strengths in information technology—specifically silicon chips and semiconductors—will catapult them to the fore of healthcare innovation. “In the Asia-Pacific region, they’re building tomorrow’s healthcare system today,” Burrill said. He characterized the future of biotech as “Silicon Valley meets physics,” leading to greater opportunities.

The Players

Joe Panetta, president and CEO of BIOCOM, recommended taking advantage of Asia’s strengths to conduct innovative research and development in that region. Although China, India, and Singapore are the trendiest Asian destinations, they’re hardly the only players. “Japan and Australia have mature pharmaceutical industries and markets; and Korea, Taiwan, Malaysia, and Thailand are seeing momentum. Indonesia and the Philippines are good as cost-reduction strategies,” but need to adapt global standards, according to Peter J. Claude, advisory partner, PriceWaterhouseCoopers.

Peter Beattie, former premier of Queensland, Australia, referenced a recent McKinsey Report that listed Korea as a hot spot for stem cell work “ahead of, or on par with, the rest of the world.” Korean representatives, in a separate session, cited the beginnings of ventures between local and international firms.

Asia is not homogeneous and, Claude stressed, “the choice of location is crucial.” For example, Cambodia is low-cost, but is very risky. Taiwan has a strong IT and medical-device culture, and the government is now offering incentives to biotech, in a bid to become a hub for CRO action, Claus said. India holds the promise of a vast future market, but that market currently is smaller than that of Japan, Korea, or China. “India and China will spearhead the growth in the Asian pharmaceutical and biotech markets,” he added, “and Singapore will maintain its position as a center for research and innovation.”

To compare multiple locations, he suggested a formula that balances costs (including compensation, infrastructure, taxes, and regulatory considerations) against the risks (geopolitical, human capital, legal, economic, and infrastructure) and market opportunities (healthcare needs, pharmaceutical market size, and the market growth rate).

“There’s no one-size-fits-all strategy. Different companies—and even different activity centers in the same company— may have different results in going to Asia,” Claude continued. Choose locations based upon your own company’s strategy, and the strengths and weaknesses of its own programs and those of potential locations.

Deals with Asian partners offer several strategic benefits. Most obviously, they open vast potential markets. Beyond that, they also offer specific expertise, a market for mature Western therapies and, even in today’s constrained economy, sources of financing.

Cost ranking of Asian territories

Capital

“The IPO window is absolutely closed,” stated Lisa Walters-Hoffert, managing director, Roth Capital Partners. That limits both the number and size of deals as venture firms work to ensure they can honor existing commitments. Zhu Shen, Ph.D., founder and CEO of BioForesight, suggested that the IPO window may open in China late this year or in early 2010 for companies listing on local stock exchanges.

“In China and India, CROs are looking for alliances and acquisitions to expand,” Dr. Shen commented. “They’re not alone.” To fill the void left by the dearth of IPOs, “we’re seeing a wave of companies looking for strategic deals,” added Vivian Lee, partner at Aqua Partners. “Companies are looking at ways to move up the food chain from their traditional businesses,” and that often means collaborations, mergers, and acquisitions. Importantly, that interest is flowing both ways across the Pacific. WuXi, for example, acquired the U.S. based Apptech Laboratory Services last year.

Currently, Chinese CROs and firms focused on plasma, biologics, preclinical services, and clinical trials services will see opportunities to consolidate and participate in some cross-Pacific acquisitions. “The blood-supply industry is growing tremendously and is exporting products outside of China,” Nancy Chang, chairman and senior managing director, Asia, Orbimed Healthcare Fund Management, explained. In a move to ensure quality, “the government is forcing consolidation in the plasma industry,” by mandating that blood collection centers be closely affiliated with major plasma companies.

Japan is also seeing some acquisition activity. “The Japanese acquiring company allows a fair amount of independence,” according to George Montgomery, managing director at Montgomery, Marshall Healthcare Partners. “That’s indicative of a trend in M&A for more balanced risk sharing.” Typically, the acquiring firm provides a sufficient up-front payment to wrest control from the venture capital companies and then makes milestone payments.

Citing last year’s acquisition of Ranbaxy Laboratories by Daiichi Sankyo, Montgomery said that Japan is looking to India, China, and Europe, hedging bets regarding healthcare reform in the U.S. with potentially huge Asian markets. “They’re taking the long view. To be a global player, you have to serve India and China,” Montgomery reiterated.

Korea, historically, has served its domestic market and now wants to expand, according to Sang Chul Kim, general director of the Korean Trade Investment Promotion Agency. The country plans to boost government R&D investment in biotech from $836 million in 2006 to $3.3 billion in 2016, and to grow the market from $1.4 billion to $25 billion in that same time frame. It also plans to nearly double the number of graduates from master’s and doctoral programs to 17,300 and attain seventh place rankings for its quantity of scientific publications and patent filings by 2016.

“In 2009, for the first time, government spending on biotech was larger than IT spending,” Kim said. The government of Korea also has established a new, $100 million fund for biotech investment. “Ten to twenty percent of the seed money is from the government, and the rest is raised from the private sector,” Kim added.  “International venture capital firms will manage the fund.”

In addition to trans-Pacific investment by individual companies, some foreign capital funds are seeking to develop international strategies by investing in North American and European companies. Takeda Research Investment, the corporate venture arm of Takeda Pharmaceutical, for example, initially wanted to expand its footprint into the U.S. and Asia, and now is expanding into other regions also.

According to Juan Harrison, vp, Takeda specializes in early investments. “We don’t put in much money,” he admitted, “but build collaborations among investment groups to provide undiluted funds.” As other venture-capital firms favor late-stage investment, “it’s more and more difficult to put these syndicates together.”

To attract foreign capital, the rule of thumb is to partner with a local company or to locate significant activities locally. That’s especially true in India. Anula Jayasuriya, managing director, Evolvence India Life Science Fund, said she raised a small $100 million fund in Europe and the Middle East to invest in India. “We will look at cross-border deals that have a significant presence in India,” she added.

Other funds with a similar approach, she pointed out, include Venture East for India, and for China, Fidelity Ventures and Orbimed Healthcare Fund Management. Hong Kong based Morningside Ventures is another. Rachel Gong, healthcare investment, said that she has invested Hong Kong capital in the U.S. and China for more than a decade.

Partnering

Cost ranking of Asian territories

When partnering abroad, it’s vital that the partnership is perceived as having strategic business importance, stressed Anand Govindaluri, CEO of Go-Vin Holdings. Forming an alliance in the hope of attracting capital is bad business strategy. Therefore, “don’t custom make a plan just become a company has money. It must make smart business sense in order to work in Asia.”

Cytori Therapeutics, for example, considered the Japanese market strategic. “For a deal to be accepted, the technology has to be relevant to the potential partner’s market,” Mark Saad, CFO, emphasized. “It’s a long time from ‘hello’ to signing a deal.” By patiently courting several Japanese firms, Cytori found a good match with Olympus that fit the strategic goals of both companies. The arrangement infused about $50 million into Cytori.

“This wasn’t a one-off deal, but a strategic decision,” Saad explains. “We found the scale we needed for a joint venture with Olympus for a product aimed at global scale. We encouraged them to go out of their usual risk profile. We were very early stage,” he said.

“It’s not easy to do business in a country like India. To begin with, it’s a 20-hour flight,” Govindaluri pointed out. Therefore, he advised having a business plan for the next five to ten years, with a structure to raise funds in Asia, match the legal structure to the environment, have your attorney with you, and consider how the new shareholders (or board members) will interact with the current set. Also, have an exit strategy that considers the positions of both sets of constituents.

Key Players and Strengths

* CROs in China and India are actively looking to expand globally.

* India holds the promise of a vast future market but needs to be built up.

* Japan has a mature pharmaceutical industry and market.

* Korea is considered, by some pundits, as a hot spot for stem cell work.

* Singapore has a strong position as a center for research and innovation.

* Taiwan and India both have a strong IT and medical-device culture.

Mithridion’s Compounds Aim to Selectively Activate M1 Receptors to Reduce Side Effects

Carol Potera, Aug 1 2009 (Vol. 29, No. 14)

Mithridion’s MCD-386 activated alpha-secretase in cultured cells in preclinical laboratory models, thus potentially reducing the production of neurotoxic A-beta and preventing neuron death in Alzheimer’s disease.

Mithridion’s MCD-386 activated alpha-secretase in cultured cells in preclinical laboratory models, thus potentially reducing the production of neurotoxic A-beta and preventing neuron death in Alzheimer’s disease.

The pipeline at Mithridion in Madison, WI, consists of treatments for Alzheimer’s disease and other central nervous system disorders. Company scientists are focused on improving first-generation drugs that target muscarinic receptors. Although none of the first-generation drugs ever made it to market due to unacceptable side effects that became apparent in clinical trials, those early trials confirmed that the M1 muscarinic receptor, in particular, was the best target.

“M1 agonists have the potential to not only treat symptoms of Alzheimer’s, but also to get at the underlying disease process,” says CEO Trevor Twose, Ph.D. Dr. Twose helped to found Mithridion in 2006 to advance second-generation muscarinic agonists.

The starting compounds were created in the laboratory of William Messer, Ph.D., Mithridion’s CSO and a pharmacology professor at the University of Toledo. In June 2008, Mithridion merged with Cognitive Pharmaceuticals, Dr. Messer’s virtual company. “The marriage was a good one,” says Dr. Twose, because it wedded Mithridion’s drug discovery expertise, management skills, and investor base with Dr. Messer’s pharmacology knowledge.

Certain neurons in the brain, known as cholinergic neurons, communicate through the neurotransmitter acetylcholine to control memory and cognition. In Alzheimer’s disease, cholinergic neuron function is deficient due to the death of neurons caused by the neurotoxic peptide A-beta. One kind of cholinergic receptor important for memory and cognition is muscarinic receptors, especially the M1 subtype. Other muscarinic receptor subtypes include M2, which slows the heart rate, and M3, which causes sweating, salivation, and gastrointestinal problems.

The first-generation muscarinic agonists activated several muscarinic receptor subtypes, resulting in unpleasant side effects. In contrast, Mithridion’s second-generation drugs replace the lost cholinergic function by selectively activating only M1 receptors to improve memory and cognition. This approach selectively minimizes the risk of fainting, sweating, excessive salivation, and diarrhea, common side effects that led to the demise of the first-generation drugs.

Among the first-generation drugs, Eli Lilly’s xanomeline was regarded as the best candidate, and it showed beneficial effects on symptoms in Alzheimer’s disease and schizophrenia. Now, Frank Bymaster, one of the inventors of xanomeline, is advising Mithridion about how to design better second-generation compounds.

Extensive scientific literature provides evidence that M1 agonists interact with several key pathways that contribute to the pathology of Alzheimer’s. These include a reduction in the production of neurotoxic A-beta; an increase in another peptide that protects against A-beta damage; a decrease in cell death; and a decrease in phosphorylation of tau protein.

“We don’t have proof that our compounds will modify Alzheimer’s in people, but the results from animal models are highly encouraging that our drugs interact with these pathways and should modify disease activity,” says Dr. Twose. Mithridion’s compounds appear to boost memory and cognition by targeting underlying disease processes that slow neuronal death “and that’s the ultimate goal,” he adds.

Better than First-Generation Drugs

All the compounds in the pipeline at Mithridion are small molecule oral-acting drugs. The lead candidate, MCD-386, is a selective M1 muscarinic agonist that potently activates M1 receptors, yet has weaker or negligible action on other muscarinic receptors.

In three animal models, MCD-386 improved cognitive memory functions with reduced side effects, compared to first-generation compounds. An unexpected finding was that MCD-386 also activated the enzyme alpha-secretase in laboratory models, indicating a potential reduction in the production of neurotoxic A-beta and the possible prevention of neuron death. The results suggest that MCD-386 may not only treat symptoms of Alzheimer’s disease, but also slow disease progression.

Mithridion recently presented the results of a Phase I study of 18 volunteers. In the study, MCD-386 was rapidly absorbed and reached maximum serum levels in 1 to 1.5 hours, and serum levels were linearly related to dose. No participants reported any severe side effects, but mild sweating, salivation, and flushing occurred in some participants at the highest dose.

Based on these encouraging results, Mithridion is working on a controlled- release formulation with the dual goal of extending the duration of action and avoiding elevated peak concentrations that contribute to side effects. Further Phase I trials are planned for later in 2009.

Another state-of-the-art tool, triple quadrupole mass spectrometry, gives scientists at Mithridion an advantage for working in the Alzheimer’s drug arena. Triple quadrupole mass spectrometry measures accurately and quantitatively small amounts of drugs in an extract of blood or brain tissue during preclinical studies. In Alzheimer’s disease research, it’s critical to confirm that new drug candidates are capable of crossing the blood-brain barrier to work in the brain. “The blood-brain barrier is quite an obstacle, and many drugs fail to get through,” Dr. Twose notes.

Not only does triple quadrupole mass spectrometry confirm that compounds enter the brain, but the technology also defines chemical structures required for this to happen. “We know many of the rules, so we can carry out an in silico process before we synthesize compounds,” continues Dr. Twose. Mithridion’s semi-rational approach to drug design provides a good estimate of whether compounds will pass into the brain, and triple quadrupole mass spectrometry verifies that this occurs.

Mithridion views its forte as lead optimization, and preclinical and early clinical development of small molecule drugs. As drug candidates prove themselves, the company will seek partners to collaborate on Phase III development, regulatory approval, and marketing.

Antibodies better than chemo with stem cell transplant

WEDNESDAY, Sept. 2 (HealthDay News) — For children born with immunodeficiencies, researchers may have found a better way for them to get the help they need from stem-cell transplants.

A regimen using antibodies instead of high-dose chemotherapy may help even in the sickest children, according to Dr. Persis J. Amrolia, a doctor in the department of bone marrow transplantation at Great Ormond Street Children’s Hospital in London, and colleagues. Their findings appear online in advance of publication in an upcoming edition of The Lancet.

Children with primary immunodeficiencies have genetic defects in their immune system that leave them open to infection and other complications. Stem-cell transplants can replace the defective immune system with one derived from healthy donor bone marrow, but without a stem-cell transplant, many of these children might die, the researchers noted in a journal news release.

In order to create space for the donor stem cells and prevent rejection, the patient usually undergoes chemotherapy, radiotherapy or both. This chemoradiotherapy can cause severe liver or lung damage, as well as hair loss and sickness. It may also cause problems with growth, puberty and infertility in later life, according to the news release.

In this study, instead of using high-dose chemotherapy, the researchers used immune molecules made by white blood cells (called monoclonal antibodies). The method targeted molecules called CD45 and CD52, which are specific to bone marrow and blood cells. Therefore, the monoclonal antibodies targeted only the immune cells that cause rejection and did not affect other body tissues, the authors explained.

With this approach, the 16 children with primary immunodeficiencies in this study, who were too sick for a traditional stem-cell transplant, were able to avoid much of the toxicity caused by chemotherapy.

The approach was well-tolerated despite the fact that most patients were extremely sick at the time of transplant. The researchers reported no signs of sickness or hair loss normally associated with high-dose chemotherapy and less damage to the liver and lungs.

Patients recovered twice as fast as those given standard treatment, and almost all are doing well and are expected to have few problems associated with the treatment later in life, the study authors added.

More information

Learn more about childhood immune deficiencies from the Lucile Packard Children’s Hospital at Stanford University.

by ALex Nusbaum

Facet Biotech Corp., maker of an experimental treatment for multiple sclerosis, rose more than 10 percent above a proposed bid from Biogen Idec Inc., suggesting investors expect a higher offer.

Facet’s board of directors rejected the unsolicited, $356 million bid as “inadequate,” according to a statement today from the Redwood City, California, biotechnology company. Biogen offered $14.50 a share Sept. 4. Facet also said it approved a one-year plan giving shareholders the right to buy more stock if Cambridge, Massachusetts-based Biogen pursues a hostile takeover.

Biogen, the world’s largest maker of multiple sclerosis medicines, and Facet have been developing daclizumab for the disease since 2005, as well as volociximab for cancer. Facet, which has no products on the market, rose 74 percent in Nasdaq Stock Market composite trading Sept. 4 after Biogen made the bid. On Aug. 25, Facet turned down a $15-a-share offer from Biogen and struck a partnership with Trubion Pharmaceuticals Inc. of Seattle.

“We see limited chance the acquisition is completed at $14.50 a share,” said Bret Holley, an Oppenheimer & Co. analyst in New York, in a note to clients yesterday. “We see a reasonable probability Biogen will raise the offer as Facet is a good strategic fit.”

A purchase for less than $20 a share would be “an incremental positive” for Biogen, Holley wrote.

Biogen spokeswoman Jennifer Neiman declined in a telephone interview to comment.

Facet jumped 75 cents, or 4.9 percent, to $16.13 in Nasdaq Stock Market composite trading at 10:31 a.m. and had risen 60 percent this year before today. Biogen shares rose 22 cents, less than a percent, to $51.23 after gaining 7.1 percent for the year.

“Facet Biotech and our board of directors are committed to building value for all our stockholders,” Chief Executive Officer Faheem Hasnain said in the statement. “The proposal of $14.50 per share represents only the cash on our balance sheet and fails to attribute any value to daclizumab, or to the rest of our existing R&D pipeline and platform.”

To contact the reporter on this story: Alex Nussbaum in New York anussbaum1@bloomberg.net.

Tim Dean (Australian Life Scientist) 08/09/2009

Adelaide-based drug discovery and development company, Bionomics, has put itself in a position to fund clinical trials of its two most advanced candidates through the raising of $15 million in capital.

Of that amount, $5.8 million was raised via a private placement of shares to institutional and sophisticated investors at 24c a share, which was the average price around 2 September.

Another $2.2 million comes from a share purchase plan for shareholders that has been fully underwritten by Linwar Securities.

This $8 million in capital raising satisfies one of two outstanding conditions with venture capitalist firm, Start-Up Ventures, for an additional $7 million investment in the company.

Tim Dean (Australian Life Scientist) 08/09/2009

All up, that’s a neat $15 million, which is over three times the cash position of the company at the end of the last financial year.

This money will go towards funding ongoing clinical trials of Bionomics’s two leading drug candidates, BNC105 for the treatment of various cancers and BNC210, for the treatment of anxiety. In a statement released by the company, it expects to run these trials for two or more years on the existing funding.

In the same company statement, it has been announced that chairman, Dr Peter Jonson, will retire from the board in November, to be replaced by board member, Mr Chris Fullerton.

By Robert Weisman, Globe Staff 

Life-sciences companies face a funding squeeze as pharmaceutical giants consolidate and financial markets cool toward biotechnology start-ups, industry leaders said yesterday.

“The biotechnology industry is a huge consumer of capital,’’ Peter Wirth, executive vice president at Genzyme Corp.,

Peter Wirth, Genzyme

the giant Cambridge biotechnology company, told a leadership panel at Suffolk Law School. “It takes a billion dollars to develop a drug. The critical dilemma now is how are we going to continue to pay for innovation.’’

In the past, drug development was funded by venture capital firms and other private investors in biotech and medical technology start-ups, but such backers have become discouraged by increasingly longer development cycles and a dearth of initial public offerings during the economic downturn, executives said.

At the same time, big pharmaceutical companies, which contributed funding through alliances with biotechs, have been acquiring one another, effectively shrinking the financing pool. The result is fewer bidders and joint venture partners for small and mid-size biotechs, said Steven C. Gilman, chief scientific officer at Cubist Pharmaceuticals in Lexington.

Steven C. Gilman

“As the large companies consolidate, there becomes less and less competition for investments in the medium-size companies,’’ he said. “The prices and the competition come down.’’

Yesterday’s panel was moderated by Susan R. Windham-Bannister, chief executive of the Massachusetts Life Sciences Center, in Waltham.

She said the center, created through the Patrick administration’s $1 billion life-sciences initiative, has helped to fill the funding gap through working capital loans, tax incentives, and strategic investments in start-ups. “This is an area where there are jobs,’’ she said. “And I really believe the way to get out of the current recession is by creating jobs.’’

But state money can go only so far. Wirth said more companies may have to adopt a “marathon model’’ of bringing drugs to market on their own. The previous “relay model’’ of conducting research and development and then selling it may now be broken, he said. “That model worked well until a couple of years ago, when the guy who was supposed to take the baton wasn’t there,’’ Wirth said.

Good things come in small sizes: The new Medigus medical camera alongside a pen.

The tiniest medical camera in the world, invented by an Israeli company, measures 0.05 inches, is cheap to produce and should eliminate the need for many invasive, costly and risky procedures.

Seeing is believing when it comes to many medical diagnoses, and that often necessitates invasive surgical procedures, X-rays and radioactive dyes. But what if you could just use a camera?

Medigus, an Israeli company that specializes in developing innovative endoscopic devices and procedures, has teamed up with Tower Semiconductor to produce the world’s smallest medical camera.

The device, which measures 0.05 inches in diameter, can be incorporated into endoscopes so that doctors receive a direct visual of even the narrowest lumens (cavities or channels within tubular structures) in the body. This would eliminate the need for invasive surgeries, X-rays and other costly and sometimes risky procedures.

Mounted on a disposable endoscope, the camera is also cheap to produce and doesn’t need to be sterilized after each use.

Medigus has sent out samples to various companies and hopes to begin mass distribution in the first quarter of the coming year.

The demand is already there, says Adi Frish, chief of business development at Medigus, adding: “We’ve been receiving requests on a large scale from device companies in different fields.”

Direct visualization for reliable diagnosis

Frish tells ISRAEL21c that a further advantage of using the camera is reliability. On an X-ray, doctors can only see black and white components; with dyes, they see an assemblage of colors. In contrast, cameras offer direct visualization for a much more reliable and complete diagnosis.

“Our device will provide physicians with more reliable visualization data on the status of the patient or organ,” Frish asserts. “It’s direct vision, so you can see the actual lumen, the actual body from the inside.”

That kind of specificity, says Frish, “will help the patient and physician by leading to safer, smoother procedures.”

Founded in 2000 by company CEO Dr. Elazar Sonnenschein, Medigus has pioneered endoscopic technologies for the treatment of gastro esophageal reflux disease (known more colloquially as heartburn).

Applications for the new tiny camera could include treatments for the ear, nose and throat. A camera could be inserted into the nose, obviating procedures that require that the patient be put under anesthesia.

Gastroscopy, a complex examination of the oesophagus, stomach and duodenum, that currently requires anesthesia, could become a simple process that takes just a few minutes.

A major breakthrough

The new camera is important, explains Frish, because “in the endoscopic world, the camera is the key component. The smaller the camera, the more latitude you have to mount different tools on the endoscope, such as a light or stapler. We identified that need, and with our capabilities we embarked on a project to develop this new camera.”

The technology is based on the CMOS sensors found in digital cameras, which are produced by Tower.

“It’s a very complex technological achievement, both to produce such a small sensor, as well as to assemble such a small camera,” remarks Frish. “In a camera you have objective lenses, and you have to assemble all the electronic components together into the wire. It’s a very difficult thing to achieve.”

With its potential to cut costs and risks to the patient, as well as its greater reliability in diagnostic procedures, the new camera may well have a significant impact on the entire field of medicine.

“It opens up a very interesting hatch from which physicians and companies can launch and develop new procedures,” concludes Frish, “and that’s a major breakthrough.”

By Ilana Teitelbaum , Israels21C

Matthew Herper

In a dimly lit conference room in the basement of Orlando, Fla.’s swank Peabody hotel, Patrick Soon-Shiong, the richest man in the drug business, is working his magic on a dozen doctors who are in town for the year’s biggest medical conference.

Patrick Soon-Shiong, the richest man in medicine, believes he's found an on/off switch that makes cancer spread.

Over a breakfast buffet, Soon-Shiong, 57, urges the oncologists to enroll their patients in a clinical trial of his cancer drug Abraxane, to test it against pancreatic tumors, which have resisted every new drug for decades. It’s a tough argument. The common wisdom about Abraxane, made by Abraxis Bioscience of Los Angeles, is that it’s just a souped-up version of another drug.

But Soon-Shiong soon takes another tack, saying he is going to share an idea that has been “whirling in my head for two years.” He asks the doctors to ponder one of the biggest puzzles in biology: Why is it that some cancer cells escape tumors to take up residence elsewhere in the body, allowing the disease to spread? This process, metastasis, is part of what makes cancers deadly.

Soon-Shiong argues that his decades of work on Abraxane provide part of the explanation for metastasis. And it just so happens that Abraxane is an ideal weapon against cells that have turned on their metastatic machinery. By the end of his talk the doctors are energized, if not totally convinced.

“The hypothesis is a great hypothesis,” says Ben Ebrahimi of Wilshire Oncology in La Verne, Calif., one of the doctors who was present at Soon-Shiong’s talk. “We need the clinical data to back it up.” As always, Soon-Shiong remains undaunted. “If this is real,” he says, “it is profound.”

Soon-Shiong is prone to exuberance. When Abraxane was approved in 2005, he hailed it (and still does) as a breakthrough. But it generates so-so sales of $300 million annually, roughly a tenth of what cancer drugs like Avastin and Taxotere generate–and far less than either Soon-Shiong or Wall Street projected a few years ago. In 2008 Abraxis Bioscience, the company he founded and of which he owns 80%, lost $278 million, including $159 million to dissolve a marketing partnership with AstraZeneca, on revenue of $345 million and is projected to lose $90 million more this year. Investors have driven down its stock by 60% this year. “I think he’s viewed as ‘What’s best for Patrick is what carries the day,’” sniffs Michael King of Merriman Curhan Ford, the only analyst covering the company.

No matter. Soon-Shiong, worth an estimated $4 billion, has worked an age-old formula for getting rich: Don’t give up equity. He has maintained ownership of the drug he invented; until he sold it last year he gave up little equity in the hospital generic injectables business he founded in 1997. He’s the only drug researcher who’s a billionaire. The other members of The Forbes 400 to come from the drug business are an expert marketer and executive (Michael Jaharis), a venture capitalist (Randall Kirk) and the founder of a generics firm (Phillip Frost.)

Soon-Shiong was born in South Africa in 1952 to parents who had fled China during World War II. At 23 he got an M.D. from the University of the Witwatersrand in Johannesburg. After a residency in surgery, he was recruited by UCLA Medical School. He soon displayed a zealousness for finding cures for illnesses that other doctors prefer to treat. He performed the school’s first pancreas transplant for a woman with diabetes, a radical–and successful–surgery for something usually treated with insulin.

Impatient with the pace of diabetes research, he left UCLA to start his first company. He performed a pioneering implant of insulin-producing cells in 1993. He gained widespread notice, but some colleagues weren’t impressed and the procedure wasn’t replicated.

Soon-Shiong soon went in another direction. His diabetes work led him to understand how to create a drug that would get directly into cancer cells, which were a lot like the stem cells he was studying in diabetes. In 1993 he invented Abraxane. It’s a variation on the well-established breast cancer drug Taxol, which works by inhibiting cell division.

Rejecting money from venture capital funds, Soon-Shiong found a different way to pay for the expensive clinical trials required to get Abraxane approved by the Food & Drug Administration. At the time, he was starting a company to sell injectable cancer drugs and antibiotics to hospitals. He used profits from that company, American Pharmaceutical Partners, to fund Abraxane’s development in breast cancer. APP went public in 2001.

Soon-Shiong said he would get Abraxane approved via an FDA rule that would let him use just one clinical trial. Wall Street was skeptical about the shortcut. At one point in 2003 the short interest in American Pharmaceutical Partners climbed to 100% of the available shares. When the FDA approved the drug in January 2005, the stock jumped 30% in a day. A gloating Soon-Shiong gives away plastic mementos displaying that day’s stock chart.

He sold APP last year to Fresenius, a German dialysis company, for $5.6 billion, of which he got $3 billion. His 80% share in Abraxis Bioscience is worth another $860 million.

A 2005 article in the Annals of Oncology called Abraxane “old wine in a new bottle.” The old wine, paclitaxel, was cancer’s first $1 billion drug and sold by Bristol-Myers Squibb under the Taxol name. Since the patent expired in 2000, the market has shifted to the generic version.

Taxol comes dissolved in a solvent so potent it melts standard iv tubing. Abraxane instead coats the drug molecules in albumin, one of the main proteins in egg white. This prevents any allergic reaction and allows the drug to be given in 30 minutes instead of three hours. Abraxane’s wholesale cost is $5,100 a dose every three weeks, which is 16 times as much as generic paclitaxel. “Definitive studies to show it is better than Taxol have yet to be done,” says Eric Winer, a top breast cancer researcher at the Dana-Farber Cancer Institute. Nor has Abraxis finished the studies required to get Abraxane approved for use in any other cancer. Results in lung cancer are expected soon.

But Soon-Shiong says his drug is more effective than Taxol, precisely because of a quirk in the albumin coat. Therein lies Soon-Shiong’s next scientific adventure: stopping cancer from spreading from, say, the breast, where it won’t kill, to the brain, where it will.

He argues that a chemical called Sparc (secreted protein acidic and rich in cysteine) is the culprit, leading smoldering cancers to suddenly spread like wildfire. Sparc has long been implicated by researchers in the spread of colon cancer to the liver and may be similarly predictive in melanoma, breast cancer and glioblastoma, a type of brain tumor.

Soon-Shiong argues that when a cell starts making Sparc, suggesting it’s about to spread, it also starts sucking in albumin-soaked Abraxane, which, he says, will kill the tumor. By studying whether Abraxane works in pancreatic cancer, where many cells are churning out Sparc, he will be able to help solve the mystery of metastasis. “We’ve been trying to shoot cancer from across the ocean,” he says. “I think we have penetrated all the way to the heart of the tumor itself.”

Patients whose cancers are churning out the Sparc protein usually have a worse prognosis, but with Abraxane they may do just as well, Soon-Shiong argues. Preliminary analysis in four different cancers indicate that Sparc-positive patients are as much as three times more likely to benefit.

Soon-Shiong offers up a list of scientists who he says are excited by his theory of metastasis. Wishful thinking. Several protest that the evidence needs to be published and that they have not seen data but just had interesting discussions. Magic bullets for understanding metastasis “have been proposed again and again, and nothing has ever held up,” says Richard Klausner, former head of the National Cancer Institute and now a principal at the Column Group, a venture capital firm. “It’s a great idea, but it’s not like when I heard the biology of it I’ve said, ‘Aha, this makes sense.’ Let’s see the data.”

Now Soon-Shiong is starting yet another company: Abraxis Health will get a $25 million equity infusion and a $200 million line of credit from Abraxis Bioscience to delve into the diagnostics business, probably beginning with a test for his metastasis marker. “If the Sparc hypothesis proves to be true and it changes the course of medicine, it would be more satisfying than all the money we ever made,” he says.

Soon-Shiong, who is married to Michele Chan, a 1980s television actress (in shows like MacGyver), says he plans to start giving more to charity now that he has sold APP. The first big gift, of $100 million, went to Saint John’s Health Center, which is associated with UCLA.

He has given up the chief executive spot of Abraxis Bioscience to Lonnie O. Moulder, who built tiny MGI Pharma, maker of an antinausea drug, into a successful biotech. In September Abraxis Bioscience picked up analyst coverage for the first time in a decade. King, at Merriman Curhan Ford, gave the company a buy rating–predicated on the beaten-down share price and the idea that Soon-Shiong will be absent from the company he founded. Soon-Shiong shrugs and says, “I think of myself as a physician trying to solve problems.”

News source: Business Wire

Applied NeuroSolutions, Inc. (OTCBB:APSN)(www.AppliedNeuroSolutions.com), a biotechnology company focused on the development of products for the early diagnosis and treatment of Alzheimer’s disease (“AD”), today confirmed, as previously disclosed in July 2009, that it has achieved sufficient analytical sensitivity to detect tau in serum patient samples. This is a key step in the development of a blood-based test to detect AD at an early stage. Based on a further analysis of the preliminary data, the Company believes additional development of the assay, including optimization and validation in key patient population groups, is necessary to determine the specific sensitivity and specificity performance of the assay. The Company is currently raising funds to support continued development and commercialization of this blood-based Alzheimer’s test.

Applied NeuroSolutions, Inc. also announces the Company website has been updated, including a current Corporate Presentation.

About Applied NeuroSolutions:

Applied NeuroSolutions, Inc. (OTC BB:APSN – News) is developing diagnostics and therapeutics to detect and treat Alzheimer’s disease (AD) building on discoveries originating from the Albert Einstein College of Medicine. Applied NeuroSolutions is in a collaboration with Eli Lilly and Company to develop novel therapeutic compounds to treat the progression of AD. For its diagnostic pipeline, Applied NeuroSolutions is focused on both cerebrospinal fluid (CSF) and serum tests to detect AD at a very early stage. The CSF based P-Tau 231 test now being offered for use in clinical trials can effectively differentiate AD patients from those with other neurological diseases that have similar symptoms. There is currently no FDA approved diagnostic test to detect AD. Alzheimer’s disease currently afflicts over five million Americans, and the world market for AD therapy is currently estimated to be nearly 30 million patients. For more information, visit www.AppliedNeuroSolutions.com

This press release contains forward-looking statements about Applied NeuroSolutions. The company wishes to caution the readers of this press release that actual results may differ from those discussed in the forward-looking statements and may be adversely affected by, among other things, the risks associated with new product development and commercialization, clinical trials, intellectual property, regulatory approvals, potential competitive offerings, and access to capital. For further information, please visit the company’s website at www.AppliedNeuroSolutions.com, and review the company’s filings with the Securities and Exchange Commission.

M. D. Anderson Cancer Cente

SAO PAULO, BRAZIL ― A team of researchers led by The University of Texas M. D. Anderson Cancer Center unveiled results today from the largest-ever collaborative study addressing the treatment of a rare pediatric brain tumor. The findings suggest a new standard protocol could improve survival nearly two-fold for pediatric patients with choroid plexus tumors, as reported at the 41st Annual Meeting of the International Society of Pediatric Oncology (SIOP).

Johannes Wolff, M.D., professor in the Children’s Cancer Hospital at M. D. Anderson Cancer Center and lead investigator on the study, revealed that the protocol, consisting of three chemotherapy agents and radiation, had projected overall survival rates of 93 percent at one year, 82 percent at five years, and 78 percent at eight years.

“This SIOP 2000 study started 10 years ago and has grown to include more than 100 institutions from more than 20 countries,” said Wolff. “With the data we have, we can tell which patients are prone to do better and which ones have a poor prognosis. In addition, we’ve established a promising standard protocol for these patients.”

Choroid plexus carcinomas are malignant brain tumors that originate in the choroid plexus epithelium, which is the gland that produces cerebrospinal fluid. Often the tumors may block the flow of cerebrospinal fluid causing pressure to build in the brain and possibly enlarge the skull. It is a very rare tumor affecting approximately 1,500 children worldwide each year, occurring more often in infants.

Due to the rarity of the disease, there is no standard treatment protocol for the disease, but Wolff and other international researchers hope to change that through their studies. They also developed an innovative statistical module for institutions to use that will ensure quality and efficient data coming out of the study.

One surprising finding Wolff and fellow researchers discovered contradicted historical research, which originally showed the significant advantage of complete surgical resection. The SIOP 2000 study found that patients receiving the intense chemotherapy protocol had similar outcomes as those with complete resection, reducing the need for surgical treatment.

“We think the better outcomes had to do with the fact that physicians will prolong chemotherapy treatment if there is residual tumor,” said Wolff. “If we can prove this hypothesis, this would be an argument for extending treatment in the future.”

Wolff says the next step will be to begin another study that will investigate a four-armed chemotherapy protocol. This would investigate the possibility of adding another chemotherapy to further improve survival rates. The SIOP 2000 study used carboplatinum, etoposide and cyclophosamide in combination with radiation.

The study was funded through the German Children’s Cancer Foundation.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News and World Report. About the Children’s Cancer Hospital at M. D. Anderson

The Children’s Cancer Hospital at The University of Texas M. D. Anderson Cancer Center has been serving children, adolescents and young adults for more than 50 years. In addition to the groundbreaking research and quality of treatment available to pediatric patients, the Children’s Cancer Hospital provides its patients with comprehensive programs that help the children lead more normal lives during and after treatment. For further information, visit the Children’s Cancer Hospital Web site at www.mdanderson.org/children.

By GAUTAM NAIK and MARK SCHOOFS

A Thai technician works on blood samples of test volunteers last month at a laboratory in Bangkok.

Researchers from the U.S. Army and Thailand announced last month they had found the first vaccine that provided some protection against HIV. But a second analysis of the $105 million study, not disclosed publicly, suggests the results may have been a fluke, according to AIDS scientists who have seen it.

Quest for a Vaccine

The second analysis, which is considered a vital component of any vaccine study, shows the results weren’t statistically significant, these scientists said. In other words, it indicates that the results could have been due to chance and that the vaccine may not be effective.

The additional data were available to the researchers on Sept. 24 when they announced the trial results, but they chose not to disclose them, said Jerome Kim, a scientist with the U.S. Army who was involved in the study. News of the second analysis was first reported on the Web site of Science magazine, but the story didn’t provide specific data. Full details of the trial are to be aired at an AIDS meeting in Paris that starts Oct. 19.

The incomplete disclosure raises the question of whether the Army, the Thai government and the U.S. National Institutes of Health — which helped fund the study — rushed to give a positive spin to what may turn out to be another inconclusive AIDS-vaccine effort.

“We thought very hard about how to provide the clearest, most honest message,” Dr. Kim said. “We stand by the fact that this is a vaccine with a modest protective effect.” He called the trial results “complex.”

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, the part of the NIH that oversees AIDS research, declined to comment.

The study was criticized as pointless by some AIDS scientists when it was launched three years ago because it combined a failed vaccine with one widely thought to have little chance of success. It was the largest HIV vaccine trial ever conducted, with more than 16,000 participants in Thailand.

Some AIDS researchers and activists who have learned of the additional data still think the vaccine shows promise and should be investigated further. But they worry that not disclosing the study transparently will cause people to conclude the vaccine trial was a failure and undermine support for more research.

A Thai technician works on blood samples of test volunteers last month at a laboratory in Bangkok.

“I would have preferred to have seen both results straight up. It might spring back on them, and that would be unfortunate,” said Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition in New York.

About 33 million people were living with HIV world-wide in 2007, according to the latest United Nations statistics. About two million people died from AIDS that year. There have been more than 100 HIV vaccine trials since 1987. None had succeeded until the latest Thai trial.

The results announced last month were based on a “modified intent to treat analysis,” which includes virtually everyone who enrolled in the study, regardless of whether they ended up getting the full course of the vaccine. It is a good stand-in for the real world, where people don’t always follow instructions properly. By this measure, the vaccine tested in Thailand reduced by 31% the chance of infection with HIV, the AIDS-causing immunodeficiency virus.

But the result was derived from a small number of actual HIV cases: New infections occurred in 51 of the 8,197 people who got the vaccine, compared with 74 of the 8,198 volunteers who got placebo shots. Statistical calculations showed there was a 3.9% probability that chance accounted for the difference. In drug and vaccine trials, anything above a 5% probability of a chance result is deemed statistically insignificant.

The second analysis is called “per protocol” and adheres strictly to how the trial was designed by only including the study participants who got the full regimen of vaccine shots at the right time. Because it excludes study participants who didn’t get the full vaccine regimen, it usually provides corroboration to the looser “intent to treat” findings.

Two AIDS scientists, who have seen the “per protocol” analysis, said it indicates there is a 16% chance the study results were a fluke — a far greater probability than is considered statistically acceptable. This analysis included 86 people who received either the vaccine or a placebo and were infected. The “per protocol” analysis also showed that the supposed effectiveness was lower, at 26.2%. Dr. Kim, of the U.S. Army, declined to comment on the data. It isn’t clear why the vaccine was seemingly ineffective among participants who followed the guidelines to the letter.

These anomalous results sparked discussion last week at a meeting of the Center for HIV-AIDS Vaccine Immunology in Durham, N.C. The group is made up of a team of universities and academic medical centers established by the NIH to help vaccine design and development.

“I think in general it’s best to lay out as much data as possible,” said Barton Haynes, director of the center and an HIV vaccine expert at Duke University, who was at the meeting. “This is a very difficult situation for everyone, and we’ll have to wait until all the data are released so we can drill down into it.”

When drug or vaccine trials results are disclosed, it is common for investigators to simultaneously provide “per protocol” and “intent to treat” data. For example, when Merck & Co. announced the details of its failed HIV vaccine trial in 2007, the Whitehouse Station, N.J., company provided both sets of statistics at the same time.

In September, the AIDS Vaccine Advocacy Coalition published a report in anticipation of the Thai results that noted: “The safest route is to report both PP [per protocol] and ITT [intent to treat] and to analyze the difference.”

In January 2004, a group of 22 scientists in article in the journal Science noted that one component of the Thai vaccine, a primer dose made by Sanofi Pasteur, a division of Sanofi-Aventis SA of France, was poor at triggering an immune response. They also pointed out that trials of the second component of the Thai vaccine, a booster component now licensed to Global Solutions for Infectious Diseases, of South San Francisco, Calif., had been proven “to be completely incapable of preventing or ameliorating HIV-1 infection.”

They added: “One price for repetitive failure could be crucial erosion by the public and politicians in our capability of developing an effective AIDS vaccine collectively.”

Write to Gautam Naik at gautam.naik@wsj.com and Mark Schoofs at mark.schoofs@wsj.com

Associated Press

Vaccine-like shots to keep cocaine abusers from getting high also helped them fight their addiction in the first successful rigorous study of this approach to treating illicit drug use.

The shots didn’t work perfectly, but the researchers said their limited success is promising enough to suggest the intriguing vaccine approach could be widely used to treat addiction within several years.

“It is such an important study. It clearly demonstrates … that it is possible to generate vaccine that could interfere with cocaine actions in the brain,” said Nora Volkow, director of the National Institute on Drug Abuse, which funded the study.

The results come just days after plans were announced for the first late-stage study of an experimental nicotine vaccine designed to help people quit smoking .

The NicVAX vaccine has been fast-tracked by the Food and Drug Administration, and the resear ch will be paid for with federal stimulus money .

The cocaine and nicotine vaccines both stimulate the immune system to produce antibodies that attach to molecules of the drugs, blocking them from reaching the brain.

In the new study, cocaine-fighting antibodies helped prevent users from getting a euphoric high and led nearly 40% of them to substantially cut back or stop cocaine use, at least temporarily.

Thomas Kosten of Baylor College of Medicine in Houston developed the vaccine used in the study, which is in October’s Archives of General Psychiatry, released Monday.

Dr. Volkow said that the research exemplifies a “transformative” perspective on drug addiction.

“By targeting it as a medical disease as opposed to a moral dilemma, we’re likely to come up with solutions that have a much longer impact,” she said.

The research involved 115 cocaine abusers also addicted to heroin who sought methadone treatment at a New Haven, Conn., clinic. Methadone treats heroin addiction, not cocaine, but it requires repeat clinic visits. That made it easier for the researchers to work with and track the cocaine abusers, Dr. Kosten said.

Over 12 weeks, nearly all participants got five shots of cocaine vaccine or a dummy substance. They were followed for an additional 12 weeks. All participants also attended weekly relapse-prevention therapy sessions, and had their blood tested for antibodies and their urine tested for cocaine and heroin.

Overall, 21 vaccine patients—38%—developed cocaine antibody levels high enough to prevent a cocaine high. In this group, 53% stopped using cocaine more than half the time during the study, versus 23% of those with lower antibody levels.

The researchers plan a larger study next year, Dr. Kosten said.

Despite the limited success, the results are exciting and show that the vaccine approach is a good one, said Kyle Kampman, a University of Pennsylvania addiction researcher who wasn’t involved in the study.

“We need novel approaches because cocaine dependence is a disease that has been very difficult to treat,” Dr. Kampman said.

Copyright 2009 Associated Press

EUREKALERT

Boston, Mass. Alcohol and drug use are known contributors to adolescents engaging in dangerous sexual activity; leading to substantial health risks such as unwanted pregnancies, sexually transmitted illnesses, drug overdoses and alcohol poisonings. Yet, research suggests that fewer than half of pediatricians report screening patients for substance use and at-risk sexual behavior. CRAFFT, the diagnostic test developed and currently being employed at Children’s Hospital Boston, allows primary care physicians to accurately screen teens for high risk drug and alcohol use in a matter of minutes. Now, according to a new study appearing in the Journal of Adolescent Health, Children’s researchers have established that the CRAFFT diagnostic test can also identify teens that are more likely to be engaging in high risk sexual behaviors.

The studies researchers found that teens who screened positive for substance use had significantly greater odds of having sexual contact after using drugs or alcohol. According to the findings, these teens were more likely to have unprotected sex, multiple sexual partners and even a sexually transmitted illness. The cross-sectional survey consisted of 305 adolescents from ages 12- to 18-years-old in 3 different urban clinics. Participants were asked the CRAFFT questions, and also completed a self-administered questionnaire about high risk sexual behaviors. Of those who screened positive, 42.6% reported having sexual contact without a condom, 26.1% after drinking alcohol, 15.6% after drug use and 21.7% with a partner who had been drinking alcohol.

Developed by the Children’s Center for Adolescent Substance Abuse Research, the CRAFFT screen, which refers to the mnemonic acronym in the six screening questions, includes questions such as “do you ever use alcohol or drugs to relax, feel better about yourself, or fit in?” and “do you ever forget things you did while using alcohol or drugs?” Answering “yes” to two or more questions is highly predictive of an alcohol or drug-related disorder and now at-risk sexual behavior.

“Primary care physicians are on the frontline of identifying adolescents who are at-risk and all should be screened with questions like these at every routine medical visit,” says Sharon Levy, MD, co-author of the study and physician in the Adolescent Substance Abuse Program at Children’s. “Clinicians should be prepared to discuss high risk sexual behaviors with their patients along with the dangers of engaging in sexual activity while intoxicated. Something as simple as asking an adolescent a few questions during a clinical appointment might make the difference.”

The CRAFFT test is routinely administered during adolescent clinical appointments at Children’s. All adolescents who take the test receive brief advice on alcohol and drug use, and those who test positive are recommended to further assessment for substance use disorders. The authors suggest that these adolescents also receive counseling to avoid high risk sexual behaviors and sexual activity after alcohol or drug use.

Contact: James Newton
james.newton@childrens.harvard.edu
617-919-3110
Children’s Hospital Boston

By Shannon Pettypiece and Andrea Gerlin

Oct. 15 (Bloomberg) — Pfizer Inc. may slash as much as $3 billion in research after combining its laboratories with Wyeth, putting thousands of scientists out of work and narrowing the drugmaker’s search for new products.

With the $68 billion deal closed, Pfizer will probably trim its combined research budget, Martin Mackay, president of Pfizer Global Research and Development, said in an interview. While Mackay didn’t say by how much, Pfizer may hold the line at about $8 billion, the same as it spent by itself in 2008, said Barbara Ryan, a Greenwich, Connecticut-based analyst for Deutsche Bank, in a telephone interview. That’s 30 percent less than the total both companies spent on research last year.

Pfizer has trimmed jobs and limited the diseases it studies in the last two years to save money as it braces for the loss of $10 billion in sales when its Lipitor cholesterol pill faces generic competition in 2011. While Pfizer Chief Executive Officer Jeffrey Kindler said he bought Wyeth to help offset those losses, the drugmaker’s ability to innovate over time may be diminished with fewer scientists to find new treatments, said Kenneth Kaitin, of Tufts University in Medford, Massachusetts.

“These big acquisitions don’t do a thing for research,” said Kaitin, director of the Tufts Center for the Study of Drug Development. “I don’t think anyone should be fooled into thinking these big acquisitions have anything to do with innovation or increased research and development capacity.”

Nine Areas

Pfizer, the world’s biggest drugmaker, has narrowed its drug-development focus to nine disease areas led by cancer, brain disorders and diabetes. It has trimmed its scientific programs on heart failure, high cholesterol and obesity. The New York-based company also reorganized its research centers so that each area of therapeutic research is based at one location.

Over the short term, Pfizer is close to meeting its goal of having 24 to 28 products in late-stage development by December, Mackay said in an Oct. 2 interview. That includes a pill developed for rheumatoid arthritis, CP- 690550, which could generate $1.5 billion annually, said Cowen & Co. analyst Craig Gordon. Existing treatments for that disease are injected.

Such late-stage products, though, have been years in development. Since 2007, the company has fired more than 2,000 researchers and closed laboratories in Michigan, Japan and France. While the Wyeth purchase may help Pfizer offset the loss of Lipitor revenue initially, the research cuts may challenge the combined company’s long-term growth, Kaitin said.

“This is just a delaying tactic, it doesn’t increase output in terms of research,” Kaitin said. “This is a survival technique for big pharma.”

Joint Operations

Pfizer and Wyeth will begin joint operations tomorrow, Pfizer said today in a statement. Wyeth shares will stop trading today and each outstanding share of Wyeth will be converted to $33 in cash and 0.985 of a Pfizer share.

Moody’s Investor Services lowered its long-term rating of Pfizer to A1 from Aa2. Fitch Ratings dropped Pfizer’s long-term issuer default rating to AA- from AA.

Mackay, in an interview at the company’s Sandwich, England, laboratories, said that while no final figure has been reached, the combined research budget would be reduced. The drugmaker will review projects in the next six weeks, said David Roblin, who heads the Sandwich laboratory where Viagra, Pfizer’s top- selling erectile drug, was invented.

Scientists at the two companies aren’t permitted to exchange information about their work until the merger is completed, and are “desperate” to talk, Roblin said Oct. 2.

“As soon as the close happens, the phones will be red hot,” Roblin said. “It’s an exciting time for scientists because there’s nothing like new data.”

Potential Targets

The company looked at more than 100 potential acquisitions before deciding to buy Wyeth, Mackay said. The merged company, he said, will focus on cancer, pain, neurological disorders, heart and circulatory diseases, diabetes, infectious diseases and antibacterials and vaccines.

Pfizer rose 29 cents, or 1.7 percent, to $17.66 at 4:15 p.m. in New York Stock Exchange composite trading after announcing the acquisition would be completed today. Pfizer has gained 8.7 percent in the past 12 months.

Pfizer is not alone in scaling back research spending to combat sinking revenue from cheaper copy drugs. Products that now generate $137 billion in sales are expected to face generic competition during the next five years, said IMS Health Inc.

Industry Job Cuts

Johnson & Johnson, based in New Brunswick, New Jersey, said this week its research budget fell 13 percent in the third quarter compared with a year earlier. British drugmaker AstraZeneca Plc has slashed at least 700 research positions and GlaxoSmithKline Plc, also based in London, said last year it planned to eliminate as many as 850 researchers.

The proportion of sales that pharmaceutical companies spend on research may sink to 13 percent next year, from 16 to 18 percent of sales, Ryan said.

Spending cuts have resulted in a flood of scientists into the job market, said Michael Steiner, who provides financial and career counseling to pharmaceutical professionals at RegentAtlantic Capital LLC in Morristown, New Jersey. Steiner said he has more than 100 pharmaceutical clients. Many who have lost their jobs are considering teaching, consulting or working at small biotechnology companies.

Job openings at large pharmaceutical firms are scarce, and some of his clients have been looking for work for more than a year, he said.

High School Chemistry Teachers

“Pretty much all the high school chemistry jobs have been filled,” said Steiner in a telephone interview. “Some of these are people who have been at a company for more than 25 years and are now entering the job market for the first time.”

Most pharmaceutical researchers need a Ph.D. in biology or chemistry and some have medical degrees, according to the U.S. Bureau of Labor Statistics. Drugmakers also employ laboratory technicians and support staff, jobs that typically require a high school diploma or an associate degree.

In Ann Arbor, Michigan, where Pfizer closed its 2,100- person laboratory in 2008, more than a dozen ex-Pfizer employees have taken jobs at the nearby University of Michigan, the school said in 2008. Among them is Michael Wilson, who started working as a pharmaceutical researcher at Warner Lambert Co. 25 years ago on development of Lipitor, now the world’s best-selling medicine with $12.4 billion in 2008 revenue. Pfizer bought Warner Lambert in 2000.

Former Pfizer employees displaced by lab closures in Ann Arbor and Kalamazoo, Michigan, have formed at least 44 companies, according to economic development groups Ann Arbor Spark and Southwest Michigan First.

New Venture

One such company, Kalexsyn Inc., was founded by two chemists fired by Pfizer when it bought Pharmacia Corp. in 2003. Kalexsyn provides contract chemistry work and early stage laboratory research for pharmaceutical companies.

Pfizer said in January it would fire 19,000 workers, about 15 percent of the merged drugmakers’ 129,500 employees. That is in addition to the more than 14,000 positions it has eliminated since 2007. Madison, New Jersey-based Wyeth spent $3.4 billion on research in 2008 and has about 6,000 researchers. Pfizer spent $7.9 billion last year with about 10,000 scientists.

Following the Wyeth acquisition, Mackay and Mikael Dolsten, now president of Wyeth research, will divide executive responsibility for research and development at the combined company. Mackay will oversee traditional research into chemicals and Dolsten will guide development of biotechnology products derived from living cells.

Wyeth Officers Retained

“I’ve known Mikael Dolsten for some time and I’m a great admirer,” Mackay said. “The notion of us both running this organization just made a lot of sense.”

Nine chief scientific officers have been appointed to lead therapeutic and technical areas of the company’s R&D, some retained from Wyeth, Mackay said.

Mackay said he expects scientific collaborations with external partners to continue once the merger is completed.

“I don’t think we’re going to aim for the Pfizer culture or the Wyeth culture or any legacy company,” Mackay said. “To make this work in this two-division model with Mikael and I running it, collaboration is going to be at the forefront.”

The Ministry of Finance and Office of the Chief Scientist yesterday published the tender for the government biotechnology fund, announced six months ago. According to the tender documents, the government will invest $80 million in the venture.

Sources involved in the tender said that a study by the Ministry of Finance and Office of the Chief Scientist found that the government investment could be leveraged four-fold. Previously, the fund’s organizers mentioned two to three-fold leverage, and capital markets were skeptical about the target.

The tender is slightly different from the call for proposals published two months ago, as well as from the original format defined for the biotech fund. The main difference is that the fund’s manager will have to invest $75-100 million in pharmaceutical and biotechnology companies. The fund manager will be able to investment the balance of the fund in life sciences companies, including medical devices companies, at its discretion. The original breakdown called for at least 75% of the fund to be invested in pharmaceutical and biotechnology companies and only 25% in medical devices companies. Israeli venture capital funds that invest in the life sciences did not like this breakdown.

Another difference is that the tender does not stipulate that the fund must channel investment to companies in advanced clinical trials, instead giving more freedom of action to invest in earlier stage companies as well.

The deadline for candidates to submit bids for managing the biotech fund is February 9, 2010, and the winner will be announced on March 1. The preferred candidates are venture capital funds or holding companies. Pharmaceutical companies with more than $500 million annual revenue may not participate in the tender.

Published by Globes [online], Israel business news – www.globes-online.com – on November 11, 2009

Merck has announced that the antagonist of the calcitonin gene-related peptide (CGRP) receptor telcagepant has met the primary end points in two Phase III trials to treat migraine, which is characterized by attacks of intense throbbing head pain that can last from 4 to 72 hours.

One study showed that the compound led to significant pain relief compared with placebo 2 hours after treatment and sustained freedom from pain up to 24 hours after treatment. A second study comparing telcagepant with rizatriptan (Maxalt; Merck) — a drug from the triptan class of serotonin receptor agonists, which are currently the standard of care for migraine — showed that fewer patients reported pre-specified adverse events (5% versus 11.2%) when given telcagepant.

The rationale for targeting CGRP receptors is based on two key clinical observations, explains Professor Andrew Russo, Director of the Biosciences Program, University of Iowa, USA. “It was almost 20 years ago that Lars Edvinsson and Peter Goadsby showed that CGRP was elevated in the jugular outflow during severe migraine attacks and that treatment with sumatriptan restored the levels to normal, co-incident with the alleviation of the symptoms. Further work from Jes Olesen’s group then showed that injection of CGRP led to the development of headaches in a small group of migraine patients. These observations point to CGRP being a key neuromodulator that may act by sensitizing glutamatergic synapses in the central nervous system, and that too much sensitization leads to migraine.”

Unlike serotonin receptor agonists, CGRP receptor antagonists do not constrict blood vessels and therefore do not seem to have deleterious cardiovascular side effects. These side effects limit the use of triptans in patients who also suffer from cardiovascular disease or uncontrolled hypertension. “In addition, since these drugs act by different mechanisms, it is likely that telcagepant and other CGRP receptor antagonists will help some patients who are not helped by triptans,” says Russo.

However, Merck is delaying its submission of a new drug application for telcagepant owing to the increased levels of liver transaminases that were observed in patients receiving the drug twice daily for 3 months in a Phase IIa study to prevent migraine. Whether this potential hepatotoxicity signal is a class effect or is specific to this compound, and its relation to the dose and frequency of administration of telcagepant, still need to be elucidated. However, if telcagepant shows comparable efficacy to triptans, with no vasoconstriction and a more tolerable side-effect profile, analysts have predicted that sales could reach more than US$1 billion per year. Recent evidence has also implicated CGRP in tumour angiogenesis (Proc. Natl Acad. Sci. USA 105, 13550–13555; 2008), therefore CGRP antagonists might also have potential in other indications.

Understanding how kangaroos repair their DNA could be the key to preventing skin cancer in the future, according to new research by Dr Linda Feketeová and Dr Uta Wille from the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology at The University of Melbourne.

Together with scientists from The University of Innsbruck, Austria, Dr Feketeová and Dr Wille are working toward reducing the number of skin cancer-related cases by investigating the chemistry behind potential skin cancer therapies.

The teams are investigating a DNA repair enzyme found in kangaroos and many other organisms, but not humans. This enzyme is very effective in repairing a particular type of DNA damage linked to many skin cancers.

“As summer approaches, excessive exposure to the sun’s harmful UV light will see more than 400,000 Australians diagnosed with skin cancer,”  says Dr Feketeová.

“Other research teams have proposed a ‘dream cream’ containing the DNA repair enzyme which you could slap on your skin after a day in the sun. We are now examining whether this would be feasible by looking at the chemistry behind the DNA repair system.”

Using highly sophisticated technology, the groups are simulating the skin’s UV exposure in the laboratory, and then analysing the DNA repair process in a specialised mass spectrometer instrument.

“We were quite surprised that the DNA’s repair process also resulted in a number of chemical by-products, which have never been seen before,” says Dr Wille”Our plan is to study these products to understand if the DNA repair enzyme could be incorporated into a safe and effective method for skin cancer prevention.”

“But there is still much to investigate before this ‘dream cream’ will be available at the pharmacy, so don’t throw out your sunscreen just yet!” adds Dr Feketeová.

This work will be published as a “hot paper” in the upcoming edition of Chemical Communications.

EDMONTON — An international team headed by a University of Alberta researcher has used stem cells to heal and protect the lungs of newborn rats – research that could help premature babies with chronic lung disease.

Dr. Bernard Thebaud’s team injected stem cells from bone marrow into the rats’ airways. Two weeks later the rodents were running twice as far on treadmills and had better survival rates.

The stems cells acted like tiny damage control factories, pumping out a healing liquid that scientists are working to understand.

“That healing liquid seems to boost the power of healthy lung cells and helps them to repair the lungs,” said Thebaud, who is also a specialist at Edmonton’s Stollery Children’s Hospital neonatal intensive care unit.

“The human implication is that we envision a stem cell-based treatment for these babies that suffer from chronic lung disease.”

Babies who are born extremely prematurely can’t breathe on their own and need help for their lungs to develop properly. About half of babies born before 28 weeks get chronic lung disease, a condition that can affect lung capacity as they grow up.

Thebaud and his team’s findings are to be published Dec. 1 in the American Journal of Respiratory and Critical Care Medicine and are already attracting international attention. The team included researchers from Montreal, France and the U.S.

“I want to congratulate Dr. Thebaud and his team,” said Dr. Roberta Ballard, a professor of pediatrics at the University of California. “In a few short years I anticipate we will be able to take these findings and begin clinical trials with premature babies.”

Stem cells can develop into different cell types in the body. They can act as an internal repair system, dividing to replenish other cells.

The team, which is partly funded by the Alberta Heritage Foundation for Medical Research, is now looking at the longer-term safety of using stem cells for lung therapy. There is some concern that stem cells could transform into tumours because they have the potential to become any type of cell.

Researchers want to see if the rats show any signs of cancer after they are treated.

The team is also studying the healing liquid produced by the stem cells.

Thebaud said it may be possible to use that liquid on its own to repair and heal the lungs, making the injection of the cells unnecessary.

“Now the million-dollar question is ‘What are (the cells) producing and can we harness that? can we use it as medication?”‘ he said. “We could take that fear out of the equation.”

During the research project Thebaud said he spent many hours peering through his microscope at rat tissue and watching the rodents running on treadmills.

But the image in his mind was always of the premature babies he has treated with damaged lungs that are kept alive on ventilators.

“You see those rats running on the treadmill and you think of a kid who could be able to run with his peers, play soccer or hockey,” he said. “That’s what matters.”

Pfizer Deal Signals a Move Into Treating Rare Diseases

The world’s largest drug company is thinking small.

Pfizer said Tuesday that it had licensed the worldwide rights to a treatment for Gaucher disease, a rare genetic disorder, from Protalix Biotherapeutics, an Israeli biotechnology company.

The deal signals the start of an effort by Pfizer to enter the business of selling ultra-expensive drugs for ultra-rare diseases, a market that big pharmaceutical companies once largely ignored.

And the move will put the company into direct competition with Genzyme, the biotechnology company that already sells a drug called Cerezyme to treat Gaucher disease.

Genzyme has been struggling to recover from a severe shortage of Cerezyme brought about by manufacturing problems.

Pfizer will pay Protalix $60 million initially and up to $55 million later. The companies will split expenses to market the drug and the revenue from its sales on a 60-40 basis, with Pfizer having the larger share.

Protalix is close to filing its application for federal approval of the drug. The product, called taliglucerase alfa, could reach the market next year.

Although analysts viewed the deal as a validation of Protalix’s drug and its novel manufacturing process, shares of Protalix fell nearly 14 percent, to $8.51, apparently because investors were disappointed that Pfizer did not acquire the company. Pfizer’s shares rose nearly 4 percent, to $18.85.

Protalix makes proteins that serve as drugs in genetically engineered carrot cells that grow inside plastic bags. That is far less costly, it says, than the process used by most biotechnology companies, including Genzyme, which is to use genetically engineered hamster ovary cells growing in stainless steel tanks.

That will probably mean that Protalix’s taliglucerase will be cheaper than Cerezyme, though executives at Pfizer and Protalix declined to discuss the price on Tuesday.

Big pharmaceutical companies once tended to disregard rare diseases, preferring to develop blockbusters for common ailments like diabetes and high cholesterol. But with sales growth slowing and older blockbusters losing patent protection, the companies have become more willing, even eager, to sell specialized drugs.

“This is the first step in the pursuit of a formal strategy around orphan drugs and rare diseases,” David Simmons, president of Pfizer’s established products business unit, said in an interview.

While there might be few patients with each disease, he said, “collectively, it’s a very large patient population with a great unmet medical need.”

Besides, Genzyme has proved that even a drug for a rare disease can generate big sales if the price of the drug is high enough. Only about 5,700 people in the world are being treated with Cerezyme. But since the drug costs about $200,000 a patient each year, sales exceeded $1 billion last year.

Pfizer is not alone in pursuing treatments for rare diseases. In October, GlaxoSmithKline announced a deal with Prosensa, a Dutch company, to develop drugs for Duchenne muscular dystrophy. And in June, Novartis won approval from the Food and Drug Administration to sell its drug Ilaris as a treatment for cryopyrin-associated periodic syndrome. Only about 300 Americans suffer from that syndrome, an inflammatory condition caused by a gene mutation.

Philip Nadeau, an analyst at Cowen & Company, called the entrance of Pfizer as a competitor a “modest negative” for Genzyme. However, Mr. Nadeau said, “even Pfizer’s marketing prowess is unlikely to relieve” safety concerns some doctors have about the Protalix drug. The main concern is that because it is produced in plant cells, taliglucerase may spur immune reactions in some patients.

Genzyme’s stock rose a bit less than 1 percent, to $51.11. The company announced Monday that it had resumed shipping some newly manufactured Cerezyme. Manufacturing had been shut down in June after a virus contaminated the company’s factory in Boston.

The shortfall left Genzyme vulnerable to Protalix and also to Shire, a British drug company that is also developing a drug for Gaucher disease. Because of the shortage, the Food and Drug Administration has been allowing some patients to use the Shire and Protalix drugs even though they have not been approved.

Gaucher disease is an enzyme deficiency that can cause an enlarged liver and spleen, anemia, frequent bleeding and bone weakness. All three drugs consist of the enzyme that people with Gaucher disease are missing.

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Trellis Bioscience, Inc. announced today the granting of a worldwide exclusive license to MedImmune, LLC, the global biologics unit of AstraZeneca, to develop and commercialize Trellis’ antibodies directed against the respiratory syncytial virus (RSV).

Under the terms of the agreement, MedImmune will pay Trellis an upfront cash payment upon signing, as well as additional payments for potential development, regulatory, and commercial milestones. The total payments have the potential to reach $338 million should a product resulting from this licensing agreement reach the market. MedImmune will be responsible for all preclinical and clinical development and commercialization of Trellis’s RSV antibodies worldwide. MedImmune will also pay Trellis royalty payments based on worldwide product sales.

The RSV antibodies were discovered using Trellis’ proprietary CellSpotTM discovery platform, which allows high throughput screening of human B-cells in a multiplexed format, thus enabling rapid identification and isolation of extremely rare human antibodies produced from the B-cells of RSV infected patients.

“We are excited to partner our unique anti-RSV antibodies with MedImmune,” commented James Posada, chief business officer of Trellis. “Given the company’s deep expertise in the field of RSV, we believe MedImmune is the best possible partner for this molecule.”

“The discovery of these antibodies further validates the Trellis CellSpot platform and its ability to screen millions of human B cells to identify very rare human antibodies generated by the human body to fight infection, in this case RSV,” added Stote Ellsworth president and chief technology officer of Trellis.

About CellSpot

Trellis’s patented CellSpot platform is a high throughput, cell analysis technology that enables simultaneous measurement of up to 10 antibody characteristics from single antibody secreting cells, including probes for specificity and affinity. Raising the quality threshold in the primary screen in this manner reduces the hit rate to a level that cannot be reliably accessed without the high throughput enabled by CellSpot’s extreme assay miniaturization. With CellSpot, millions of individual antibody producing cells can be characterized in detail in a few days, generating orders of magnitude more information than conventional methods. CellSpot can thereby examine the entire human repertoire in order to identify cells producing superior antibodies. As fully human antibodies, pre-screened for lack of cross-reactivity to normal human proteins, such antibodies offer the prospect of maximal safety.

About Trellis Bioscience

Trellis Bioscience, Inc. is a private, venture-funded, antibody company focused on the discovery and development of unique therapeutic antibodies from human B cells. To exploit this highly favorable but technically difficult antibody source, Trellis developed its patented CellSpot antibody discovery platform, which enables the rapid identification of rare, superior antibodies directly from human blood. The Company is initially focused on infectious disease targets, with the lead program providing therapeutic antibodies directed against Respiratory Syncytial Virus. For additional information on Trellis Bioscience, please visit our website at http://www.trellisbio.com.

By Jennifer Thomas
HealthDay Reporter

Researchers say that a new method of bone marrow transplantation cured nine out of 10 adult patients with sickle cell disease, an inherited condition that causes bouts of severe pain, organ damage and sharply limits life expectancy.

Adults have typically not been candidates because they were thought to be too sick to handle the high doses of chemotherapy and radiation necessary to prep the body for the procedure, explained senior study author Dr. John Tisdale, a senior investigator in the molecular and clinical hematology branch at the U.S. National Institutes of Health.

Until now, transplantation was generally reserved for more resilient children, whose bodies had not yet suffered as much damage from sickle cell disease.

But the new method allows for a less grueling pre-transplantation routine, one that even adults with severe sickle cell can tolerate.

More than 70,000 Americans suffer from sickle cell disease, and it is especially common among blacks. People with the disease have abnormal, crescent-shaped hemoglobin. The abnormal cells have difficulty passing through small blood vessels, causing blockages and damaging tissues. Over time, the damage can lead to stroke and severe bouts of pain in the chest, arms, legs, chest and abdomen. Sickle cell disease also damages the kidneys, liver and spleen, leaving people, especially children, more susceptible to infection, said Dr. Lanetta Jordan, chief medical officer for the Sickle Cell Disease Association of America.

Treatments include prophylactic antibiotics to fight infections, blood transfusions and hydroxyurea, the only drug U.S. Food and Drug Administration-approved drug for treating sickle cell, Jordan said.

In the new study, Tisdale and his colleagues gave 10 patients ages 16 to 45 with severe sickle cell disease alemtuzumab, a drug used to suppress immune system T-cells; relatively low doses of radiation; and sirolimus, an immune suppressant to fight rejection. Marrow donors were siblings with matched HLA (human leukocyte antigen) markers in their blood.

None of the patients experienced graft-versus-host disease, one of the most common and potentially fatal complications of bone marrow transplants, in which the body rejects the new bone marrow.

After 30 months, all of them are alive, and nine of the patients had successful grafts and are considered cured of sickle cell disease, according to the study.

“It’s been transforming for these patients,” Tisdale said. “These were the sickest of the sick patients. Some were in the hospital every other week for pain or other crises. Today, some have gone back to school and to work. One patient had a baby.”

The last item is important, because in conventional bone marrow transplants, high doses of chemotherapy drugs and radiation typically destroy fertility. However, the lower level of radiation used in the new method does not seem to do this.

The study is published in the Dec. 10 issue of the New England Journal of Medicine.

Conventional bone marrow transplants cure sickle cell disease by first using chemotherapy and radiation to wipe out the person’s own marrow, which makes the faulty red blood cells. The marrow is replaced with stem cells from a donor’s marrow, which then takes over and begins to produce new, healthy red blood cells.

But when doing the new bone marrow transplants, the researchers noted that not all of the patient’s own marrow was wiped out. Some remained and seemed to co-exist with the donor marrow without causing problems, Tisdale said.

“That meant we didn’t necessarily have to kill the entire bone marrow of the patient to make this work,” Tisdale said, opening the possibility of using an even less toxic means of preparing the body for transplant.

Though most patients in the study are still taking immune-suppressant drugs, researchers hope to eventually wean them off the medications.

Dr. Miguel Abboud, a pediatric hematology/oncology specialist and a professor of pediatrics at the American University of Beirut Medial Center, in Lebanon, said the new protocol is promising, especially since it could eventually include those who don’t have an HLA-matched sibling.

“The findings are very significant because adults with very severe sickle cell disease have decreased life expectancy and multiple morbidities but have limited therapeutic options,” said Abboud, who wrote an accompanying editorial. “In the past these patients were excluded from transplant studies as they are very poor candidates for high dose chemotherapy regimens. This study makes it possible to offer this subset of patients with severe sickle cell disease stem cell transplants.”

Dr. Lakshmanan Krishnamurti, a pediatric hematologist/oncologist at the University of Pittsburgh and director of the Sickle Cell Program at Children’s Hospital of Pittsburgh, has done bone marrow transplants in children, also using a less toxic protocol.

“This is an important paper and a big step forward for the field,” Krishnamurti said. “Now we are able to say, ‘OK, young adults or not so young adults can be transplanted successfully.’ That is a very big deal.”

Creates Pipeline With Potential Near-Term Product Launch of Dyloject(TM) and Portfolio of Early-, Mid- and Late-Stage Drug Candidates in Cancer,  HIV and Pain

SALT LAKE CITY, UT and CAMBRIDGE, MA, USA | Myriad Pharmaceuticals (Nasdaq:MYRX) today announced the company has entered into a definitive agreement to acquire Javelin Pharmaceuticals (NYSE Amex:JAV). The acquisition augments Myriad’s portfolio of product candidates with Dyloject(TM) (diclofenac sodium for injection), a New Drug Application (NDA)-submitted candidate with the potential, based on its safety and efficacy profile, to become a valuable addition to hospital formularies as an injectable NSAID for the multimodal management of moderate-to-severe postoperative pain.

Under the Agreement and Plan of Merger, Myriad Pharmaceuticals will acquire all of the outstanding shares of Javelin common stock in exchange for Myriad Pharmaceuticals stock, resulting in the Javelin stockholders owning approximately 41% of the combined company immediately after the closing. The ownership interest of Javelin shareholders may increase up to a maximum of approximately 45% depending upon the timing of FDA approval of Javelin’s lead drug candidate Dyloject. The transaction is expected to close in the first quarter of 2010. Concurrent with the closing of the transaction, Myriad Pharmaceuticals’ board of directors may be expanded to eight members, including up to two members to be nominated by Javelin.

“We believe that this transaction represents a highly effective vehicle to unlock the long-term potential of Myriad Pharmaceuticals and near-term value of Javelin Pharmaceuticals,” commented Adrian Hobden, Ph.D., President and Chief Executive Officer of Myriad Pharmaceuticals. “Myriad is well positioned to successfully launch Dyloject upon FDA approval by leveraging our financial resources and the expertise of our core commercial team. In turn, we believe that potential Dyloject revenue will support the development of our existing clinical stage drug candidates MPC-4326, Azixa, and MPC-3100.”

Martin Driscoll, Chief Executive Officer of Javelin Pharmaceuticals, added, “This agreement creates a fully integrated biotechnology company with a submitted NDA for approval of a specialty care product, Dyloject, backed by significant financial resources, a broad pipeline for growth, and a seasoned management team for future commercialization efforts.”

An NDA for Dyloject was submitted by Javelin on December 2, 2009. Dyloject is an injectable formulation of diclofenac. The development package includes data from two positive Phase 3 studies in postoperative abdominal and orthopedic pain together with safety data accrued from greater than 1,300 patients.

Diclofenac, a member of the class of drugs known as non-steroidal, anti-inflammatory drugs, or NSAIDs, is widely prescribed as an oral treatment for postoperative pain due to its combination of efficacy and tolerability. There remains an underserved medical need in the hospital setting for injectable NSAIDs that are safe, effective and fast-acting in patients unable to take oral medications. Effective use of injectable NSAIDs offers the potential to reduce opioid use and thereby accelerate patient recovery and shorten hospitalization. There is a growing demand for alternatives to opioids in the management of postoperative pain.

“Dyloject has demonstrated a very exciting profile in controlled studies showing statistically significant results in two registration trials, which have been submitted to the FDA for approval consideration earlier this month,” said Ed Swabb, Chief Medical Officer of Myriad Pharmaceuticals. “If approved, Dyloject will be an important tool in the therapeutic armamentarium for multimodal management of postoperative pain.”

Dyloject is approved and marketed in the United Kingdom by Therabel Pharma N.V. Myriad Pharmaceuticals will assume all rights to future milestone payments and royalties due from Therabel Pharma N.V.

About the Combined Pipeline

Myriad expects that, after commercial launch, Dyloject’s revenues will help support development of Myriad’s pipeline of promising clinical candidates, including:

* MPC-4326, a first-in-class small molecule inhibitor of HIV-1 maturation in Phase 2 studies for the oral treatment of HIV infection;

* Azixa(TM), a Phase 2 drug candidate being developed for the treatment of advanced primary and metastatic tumors; and

* MPC-3100, a fully synthetic, orally bioavailable inhibitor of Hsp90 in Phase 1 testing for the treatment of cancer.

Transaction Terms

Under the terms of the definitive merger agreement, Javelin shareholders will receive 0.282 shares of Myriad stock for each share of Javelin stock outstanding, representing a 16.8% premium over the average closing price of Javelin stock over the last 10 trading days. At the time of closing, Myriad will issue shares of common stock to Javelin shareholders representing approximately 41% of the fully diluted ownership of the combined company. Additional shares of common stock, representing approximately 4.1% of the fully diluted ownership of the combined company, will be placed in escrow and may be delivered, in whole or in part, to the pre-merger shareholders of Javelin, depending on the timing of FDA approval of Dyloject prior to June 30, 2011 as follows:

* If approval of Dyloject is received on or before June 30, 2010, the exchange ratio will be increased to 0.3311, representing a 37.1% premium over the average closing price of Javelin stock over the last 10 trading days.

* If approval of Dyloject is received after June 30, 2010, but before January 31, 2011, the exchange ratio will be increased to 0.3066, representing a 27% premium over the average closing price of Javelin stock over the last 10 trading days.

* If approval of Dyloject is received after February 1, 2011, but before June 30, 2011, the exchange ratio will be increased to 0.2943, representing a 21.9% premium over the average closing price of Javelin stock over the last 10 trading days.

* If approval of the Dyloject is received after July 1, 2011, the exchange ratio will remain 0.282, representing a 16.8% premium over the average closing price of Javelin stock over the last 10 trading days.

The boards of directors of both companies have unanimously approved the proposed transaction, which is subject to customary closing conditions, including receipt of required shareholder approvals of both companies.

Concurrent with the signing of the definitive agreement, the companies have entered into a loan and security agreement whereby Myriad will provide up to $6 million of interim financing to fund Javelin’s operating activities prior to closing, which is expected to occur during the first quarter of 2010.

Deutsche Bank Securities Inc. acted as financial advisor to Myriad Pharmaceuticals, Inc. in connection with the transaction. UBS Investment Bank acted as financial advisor to Javelin Pharmaceuticals, Inc.

About Myriad Pharmaceuticals

Myriad Pharmaceuticals, Inc. is a biotechnology company focused on discovering, developing, and commercializing novel small molecule drugs that address severe medical conditions, including cancer and HIV infection. Our pipeline includes clinical and pre-clinical product candidates with distinct mechanisms of action and novel chemical structures that have the potential to be first-in-class and/or best-in-class therapeutics. For more information visit www.myriadpharma.com.

About Dyloject:

Dyloject is an injectable formulation of diclofenac with a submitted NDA awaiting filing by the FDA in the United States. Dyloject is already marketed in the United Kingdom. Diclofenac is a prescription NSAID that is widely prescribed to treat postoperative pain. Dyloject has the potential to provide an attractive alternative to other NSAIDs for the management of acute moderate-to-severe pain as a single agent, and to decrease the need for morphine or other opioids in this setting. There exists an underserved medical need for safe and effective injectable NSAIDs.

NSAIDs are widely used postoperatively with opioids, e.g., morphine, to reduce opioid requirements by 30-60% and thereby decrease opioid-related side effects. Combining different types of pain medicines (called “multimodal analgesia”) is the most commonly advocated approach to acute postoperative pain management worldwide. Numerous studies of multimodal analgesia have shown that when patients are given an NSAID along with an opioid, dose requirements and adverse effects of the latter are reduced. Opioid side effects that are reduced by this dose-sparing approach include nausea, vomiting and inadequate breathing.

About Javelin Pharmaceuticals

With corporate headquarters in Cambridge, MA, Javelin applies innovative proprietary technologies to develop new drugs and improved formulations of existing drugs to target unmet and underserved medical needs in the pain management market. The company has one marketed drug in the U.K., an NDA-submitted drug candidate, Dyloject, and two drug candidates in U.S. advanced clinical development. For additional information about Javelin, please visit the company’s website at http://www.javelinpharmaceuticals.com.

The Javelin Pharmaceuticals logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6934

About MPC-4326:

MPC-4326 is being developed by Myriad Pharmaceuticals, Inc. for the oral treatment of HIV-1 infection. MPC-4326 is the first of a class of antiretroviral (ARV) drug candidates that inhibit HIV-1 replication by interfering with the maturation of the HIV-1 virus. Specifically, MPC-4326 interferes with the last step in the processing of the HIV-1 Gag protein. This inhibition leads to formation of noninfectious, immature virus particles, thus preventing subsequent rounds of HIV infection. As expected for a novel mechanism of action, MPC-4326 retains inhibitory activity against HIV-1 isolates resistant to the four classes of currently approved drugs commonly used by HIV infected patients: NRTIs, NNRTIs, protease inhibitors and fusion inhibitors. No cross-resistance has been observed.

Over 675 subjects, including over 180 HIV-infected individuals, have been studied in clinical trials of MPC-4326. Results from these trials have shown MPC-4326 to be well-tolerated and have demonstrated significant and clinically relevant reductions in viral load in a subset of HIV-infected patients representing approximately 60-70% of HIV-infected patients. This “responder” population can be identified by a simple, rapid and inexpensive assay of the HIV virus. In a Phase 2 clinical trial completed in 2008, MPC-4326 met its primary objective by demonstrating viral reduction in HIV-positive patients. In addition, the safety profile of MPC-4326 was comparable to earlier studies where that profile had been similar to placebo.

About Azixa (MPC-6827):

Azixa, MPI’s most advanced cancer drug candidate, is being developed for the treatment of advanced cancers with brain involvement. Azixa is a novel small molecule that acts as a microtubule destabilizing agent, causing an arrest of cell division with subsequent programmed cell death, or apoptosis, in cancer cells. Several currently marketed clinically effective drugs share the identical mechanism of action. Importantly, however, Azixa has two unique, distinguishing characteristics. In non-clinical studies, Azixa has demonstrated the ability to effectively cross the blood-brain barrier and accumulate in the brain at levels as much as 3000% that in plasma. In addition, Azixa does not appear to be subject to multiple drug resistance (MDR) mechanisms.

Myriad Pharmaceuticals believes that Azixa represents a unique therapeutic opportunity with the potential to treat patients with any primary or secondary (metastatic) brain cancer or any cancer that has developed resistance to conventional chemotherapeutics. Azixa is currently in clinical studies in patients with glioblastoma multiforme and metastatic melanoma.

About MPC-3100:

MPC-3100 is currently in Phase 1 clinical studies. MPC-3100 is a novel, fully synthetic, orally bioavailable, small-molecule inhibitor of Heat shock protein 90 (Hsp90). Hsp90 is a proven target for cancer treatment. Early natural product inhibitors of Hsp90 demonstrated activity in several human cancer clinical studies, including studies of Her2+ breast cancer, multiple myeloma and gastric cancers. However, these compounds have also demonstrated significant toxicity. Unlike these molecules, MPC-3100 is a fully synthetic, small molecule that is orally bioavailable and has very encouraging non-clinical safety and efficacy data. MPC-3100 has the potential to treat a wide range of cancers.

Myriad Pharmaceuticals has an issued composition of matter patent on MPC-3100 and has developed a tablet formulation. These tablets are being used in the ongoing Phase 1 study. The trial has achieved drug levels in patients which are similar to efficacious levels obtained in non-clinical studies.

Heat shock protein 90 (Hsp90) is a chaperone protein that plays an important role in regulating the activity and function of numerous signaling proteins, or client proteins, that trigger and maintain proliferation of cancer cells. Important client proteins in cancer cells include steroid hormone receptors, protein kinases, mutant p53, and telomerase. Hsp90 binds and stabilizes these oncogenes while inhibition of Hsp90 leads to their degradation.

SOURCE: Myriad Pharmaceuticals, Inc.

Multiple hormones act in concert to regulate blood sugar and food intake. The idea has already led to a new diabetes therapy; will it also yield new strategies for obesity?

By Christian Weyer ; Illustrations by Greg Betza

Stepping on the scale each day and diligently recording their caloric intake and body weight in a little booklet, my patients marked the progress and failures of their dieting efforts. It was the mid-1990s and I was working as a medical fellow in endocrinology and metabolism at the University of Düsseldorf Medical Center in Germany. During the day, we optimized insulin therapy in patients with Type 1 or Type 2 diabetes, using modern tools such as new insulin analogs, glucose meters, and insulin pumps. In the evening, I supervised an outpatient obesity clinic. Our department was internationally renowned as an accredited World Health Organization collaborating center, and patients came from far and wide to seek care for their diabetes, and a variety of obesity-related conditions.

In many respects, the work was very successful, at least in the short term. Young patients with Type 1 diabetes, many with early signs of microvascular complications, achieved their target glucose control levels for the first time since diagnosis. Obese patients, after losing 10% or more of their body weight, saw marked improvements in their liver function tests, cardiovascular risk factors, and/or sleep apnea.

But the limitations of our treatment approaches became apparent over the long term. Upon intensifying insulin treatment, most diabetes patients gained weight and many grew frustrated with the unpredictable glucose swings and constant insulin dose adjustments. Likewise, the vast majority of patients in our obesity clinic saw a relentless regain of their body weight.

In the clinical setting, it was not uncommon for doctors to advise their patients to try harder and be more disciplined. After all, with adequate willpower and meticulous tracking of blood sugars and ingested calories, there had to be a way to do better. From a scientific perspective, however, it was quite evident that the root of the problem was far more complex.

I was drawn to endocrinology because I was intrigued by the complexity and elegance with which hormonal signaling systems govern whole-body metabolism and many other vital functions. Most hormones have multiple actions that are well coordinated, and naturally integrated with other hormonal systems. It is, in many respects, the equivalent of individual musicians playing together in a philharmonic orchestra producing the most melodic, beautiful symphonies. Some hormones, such as insulin, thyroid hormone, or cortisol, are “major players,” and their deficiency or excess can result in life-threatening metabolic derangements. Others, such as calcitonin, pancreatic polypeptide, or amylin can be viewed as complementary signals that enhance, or “fine-tune,” a tightly regulated metabolic process. In many cases, the central nervous system (CNS) orchestrates and balances these hormonal interactions, serving as the role of conductor.

Working model of pramlintide/metreleptin mechanism of action, inferred from preclinical and clinical studies with monotherapy and combination therapy.

A number of important discoveries and developments occurred in the mid-1990s that ushered in a new era of endocrinology-based research and treatment approaches for diabetes and obesity. In diabetes, I had followed with great interest the emerging recognition within the medical scientific community that glucose control was governed by a number of glucoregulatory hormones other than insulin. In obesity, the whole field was electrified by a seminal discovery from Rockefeller University. Using positional cloning, Jeff Friedman and colleagues had identified a fat-derived cytokine hormone, called leptin (from the Greek word leptos, for thin). Mice lacking the leptin gene (ob/ob) displayed a slowed metabolism, a marked increase in food intake, and a profoundly obese phenotype. These abnormalities were corrected by replacing the missing hormone. This discovery not only provided scientific evidence that body weight was regulated by a complex biological feedback system, it also pointed to a pivotal role of hormonal signals in body weight regulation. Clearly, in the expanding panoply of existing and newly discovered hormones, leptin looked like a major player.

While the exact roles of leptin and some of the newer, glucoregulatory hormones—amylin and glucagon-like peptide 1 (GLP-1)—were still to be defined, I wondered whether they might be some of the “missing links” that could explain my patients’ struggles with glucose and weight control. The more I immersed myself into the evolving science, the more I felt compelled toward clinical research rather than clinical practice.

In late 1997, I moved to the United States to work as a visiting researcher with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in Phoenix, Arizona. For more than 3 decades, the Phoenix branch of the NIDDK had been conducting pioneering studies on the epidemiology and pathophysiology of obesity and diabetes in Pima Indians, a population with the highest reported prevalence rates of both disorders in the world.

With respect to obesity research, our group was world-renowned for its work on energy expenditure (metabolic rate). We conducted a series of short- and long-term studies showing that weight loss was accompanied by a prompt and sustained drop in metabolic rate and leptin levels. Seeing these results firsthand, I was convinced that the weight regain I had seen in many of my patients was not merely due to a lack of willpower, but rather the manifestation of a powerful, neuroendocrine-mediated metabolic compensation—what we call weight loss counterregulation. In other words, as people lose weight, their bodies mount a response to conserve energy and boost appetite to resist further weight loss, and eventually promote weight regain.

Virtually overnight, diabetes became a disease that was not only recognized as a multi-hormonal disorder, but could also be treated as such.

While the line of research I pursued at NIDDK contributed important insights into the pathophysiology of obesity and diabetes, there was little opportunity to translate scientific findings into novel treatment approaches.

In late 2000, I decided to join San Diego–based Amylin Pharmaceuticals, Inc., a company I had followed with interest for several years. Amylin was the only company I was aware of that was exclusively focused on developing peptide hormone therapeutics for metabolic disorders. The company had just submitted a New Drug Application (NDA) for its lead drug candidate pramlintide. It is an analog of amylin, a hormone co-secreted with insulin by β-cells in the pancreas. Amylin had emerged as a possible “partner hormone” to insulin, complementing insulin’s action in postprandial metabolism. It acts as a neurohormone that binds to receptors in the area postrema of the hindbrain. That binding slows gastric emptying via signals from the vagus nerve and suppresses excess glucagon, a hormone that normally raises blood sugar by triggering the release of glucose stores from the liver.¹ The net result is a moderation of glucose influx after a meal, to better match the rate of insulin-mediated glucose disposal.

In parallel, the company was conducting early clinical studies with a second peptide hormone candidate. This was exendin-4 (exenatide), a GLP-1 agonist that held great promise in the management of Type 2 diabetes. GLP-1, a hormone secreted by enteroendocrine cells in the gut, had the intriguing and unique ability to stimulate insulin and amylin secretion in a glucose-dependent manner—that is, only when blood glucose levels are above normal levels. Interestingly, it was noticed that both amylin and GLP-1 appeared to act as satiety signals, curbing food intake by sending a neurohormonal signal to the brain to stop eating.

In early 2005, the hard work of many came to fruition, when both first-in-class drug candidates were approved by the FDA. Pramlintide, the amylin analog, became the first novel, noninsulin peptide therapeutic for Type 1 and Type 2 diabetes in over 80 years. It helps address some of the well-known limitations of insulin therapy by reducing the excessive rise in blood sugar after a meal, erratic glucose swings, and insulin-induced weight gain.² Exenatide became an attractive alternative to injectable insulin for patients with Type 2 diabetes who were no longer able to control their diabetes with oral agents alone. It offered similar glycemic benefits to basal insulin, but with weight loss rather than weight gain, and without the inherent risk of hypoglycemia or the need for meticulous dose adjustments.³ Virtually overnight, diabetes became a disease that was not only recognized as a multihormonal disorder, but could also be treated as such.

Leptin, the once-hailed “magic bullet” for obesity, was suddenly discarded by many pharmaceutical companies as a failed target.

With both of our approved diabetes drugs having the unique attribute of reducing food intake and body weight, we ventured to tackle obesity as our next therapeutic focus. The scientific community was at that point gaining an increased appreciation that food intake and body weight were governed by a complex interplay between various hormonal signals and the brain. However, in stark contrast to the potent glucose-lowering effect of insulin and GLP-1 agonists in diabetes, no single hormonal pathway caused sufficient weight loss to be considered a therapeutic breakthrough. The once-hailed “magic bullet” for obesity, metreleptin, Amgen’s analog of human leptin, had failed to induce meaningful weight loss in people with general obesity, and was suddenly discarded by many pharmaceutical companies as a failed target.

While metreleptin treatment was not effective in inducing weight loss in patients with general obesity, several studies of rare diseases had emerged hinting at leptin’s therapeutic potential in several “low-leptin” states. Steven O’Rahilly and Sadaf Farooqi had identified a handful of children with congenital leptin deficiency caused by a frame-shift mutation in the leptin gene, named “ob.” As with the ob/ob knockout mice, these leptin-deficient (ob/ob) children displayed a voracious appetite and marked, early-onset obesity. Leptin replacement with metreleptin led to a profound reduction in food intake and body weight. Meanwhile, teams led by Phil Gorden from the NIDDK and Abhimanyu Garg from the University of Texas Southwestern, had administered metreleptin to patients with severe lipodystrophy. This rare syndrome, characterized by a severe loss of adipose tissue and a leptin deficiency, commonly manifests with extremely high circulating lipids, marked insulin resistance, and diabetes that is difficult to control even with very high doses of insulin. Metreleptin dramatically improved these metabolic problems in most patients.⁴ In a third example of patients with a “low-leptin state,” Christos Mantzoros and colleagues from Harvard demonstrated that metreleptin therapy was able to restore normal ovulatory menstrual cycles in female athletes whose menstrual cycle had stopped because of very low body fat (a syndrome called hypothalamic amenorrhea). Perhaps most relevant to the problem of weight regain in obesity, Rudy Leibel and Michael Rosenbaum from Columbia University showed that using metreleptin to restore normal leptin levels in people who had lost 10% of their body weight almost completely mitigated the counterregulatory responses that drive weight regain.⁵

As these academic clinical studies with leptin were progressing, we had established our own internal obesity research program. Rather than focusing on single-hormone pathways, we embarked on a comprehensive preclinical program in diet-induced obese rats that tested various dual- and triple-hormone combinations. Our overarching notion was that in normal physiology, food intake and body weight were not regulated by a single, predominant hormonal signal, but rather by a sophisticated interplay of hormonal signals emanating from fat cells (e.g. leptin), β-cells of the pancreas (e.g., amylin) and from cells in the gut (e.g., PYY3–36). With our team of biologists and peptide chemists, we began to systematically modify the native hormones to identify proprietary analogs that were more potent and efficacious than their naturally occurring counterparts.

The initial results from these preclinical studies were stunning to us. While most of the individual hormones induced modest weight loss, we discovered profound, additive, and even synergistic reductions in body weight when testing various dual- and triple-hormone combinations. Moreover, we identified various hormone analogs that achieved marked weight loss even when given alone. With several regimens, we could essentially normalize body weight in obese rodents. While we realized the complexities of translating these results into pharmaceutically tractable interventions, we sensed that we were onto something big. We coined the acronym INTO, for Integrated Neurohormonal Therapy for Obesity, to describe our new obesity research strategy.⁶

Among the most striking discoveries was a synergistic interaction between amylin and leptin. When given alone, leptin did not reduce body weight in obese rats, but after combining it with amylin, we saw a synergistic effect that led to marked, sustained, fat-specific weight loss (see graphic).^7,8 We reasoned that if these results would translate to human obesity, combined treatment with amylin and leptin receptor agonists (i.e., pramlintide + metreleptin) could have tremendous potential.

Though work remains to be done, our findings provide solid clinical proof-of-concept for pairing hormones that are naturally involved in the regulation of food intake and body weight.

In early 2006, Amylin licensed the exclusive rights to leptin from Amgen. Later that year, we initiated our first clinical proof-of-concept study testing the pramlintide/metreleptin combination in approximately 180 overweight and obese volunteers. All subjects followed a strict low-calorie diet for 4 weeks, then were randomized to treatment with pramlintide alone, metreleptin alone, or the pramlintide/metreleptin combination. The stakes were high. Would leptin finally show a clear weight-loss effect, after a dozen or so failed clinical trials?

In late 2007, we unblinded our study and were thrilled to find that our hypothesis on the benefits of combination therapy with pramlintide/metreleptin had borne out in humans. Overweight and obese study participants who completed 20 weeks of combination treatment (after 4 weeks on a low-calorie diet) with pramlintide/metreleptin had lost an average of 13% (>25 lbs) of weight, far more than those receiving pramlintide or metreleptin alone.⁹ Earlier this year, we confirmed and expanded our findings in a second, larger Phase 2b clinical trial (without an initial period of time on a low-calorie diet) in approximately 600 subjects, showing that pramlintide/metreleptin worked best in obese individuals with mild-to-moderate obesity. In those patients, weight loss with pramlintide/metreleptin again exceeded 10% over 28 weeks, with the vast majority of weight loss being attributable to a reduction in fat mass (approximately 20 lbs).¹⁰

Additional studies in larger patient populations are required before the therapeutic potential of the pramlintide/metreleptin combination can be fully assessed. For now, our findings provide solid clinical proof-of-concept for our strategy of pairing hormones that are naturally involved in the regulation of food intake and body weight, and which may have complementary and/or synergistic interactions.

When reflecting on the aforementioned development programs in diabetes and obesity, a number of commonalities emerge. It has become abundantly clear that body weight and glucose metabolism are both regulated by a complex interplay of multiple hormones. Understanding the interaction among these hormones, and combining hormonal signals that have additive or synergistic interactions, can lead to innovative therapeutic approaches. This concept is exemplified by amylin agonism (with pramlintide), which has been successfully developed as an adjunctive therapy to insulin for the treatment of diabetes, and has now also shown promise as an adjunctive therapy to leptin for the treatment of obesity.

While it will take years or decades before the therapeutic utility of peptide hormones in obesity are fully realized, I firmly believe that endocrine solutions will become an integral part of future treatment paradigms.

Christian Weyer, MD is the vice president of Medical Development at Amylin Pharmaceuticals, Inc.

References

1. J.D. Roth et al., “Implications of amylin receptor agonists: integrated mechanisms and therapeutic applications,” Arch Neurol, 66:306-10, 2009.

2. C. Weyer et al., “Amylin replacement as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: A physiological approach towards improved metabolic control,” Current Pharm Design, 7:1353-73, 2001.

3. J.L. Iltz et al., “Exenatide: An incretin mimetic for the treatment of type 2 diabetes,” Clinical Therapeutics, 28:652-65, 2006.

4. E.A. Oral et al., “Leptin-replacement therapy for lipodystrophy,” N Engl J Med, 346:570-8, 2002.

5. M. Rosenbaum et al., “Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight,” J Clin Invest, 115:3579-86, 2005.

6. H. Chen et al., “Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: Implications for an integrated neurohormonal approach to obesity pharmacotherapy,” Current Diabetes Reviews, 4:79-91, 2008.

7. J. Trevaskis et al., “Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: Magnitude and mechanisms,” Endocrinology, 149:5679-87, 2008.

8. J.D. Roth et al., “Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies,” Proc Natl Acad Sci U S A, 105:7257-62, 2008.

9. E. Ravussin et al., “Enhanced weight loss with pramlintide/metreleptin: An integrated neurohormonal approach to obesity pharmacotherapy,” Obesity, 17:1736-43, 2009.

10. “Amylin Pharmaceuticals announces positive results from dose-ranging clinical study of pramlintide/metreleptin combination treatment for obesity,” Amylin Pharmaceuticals press release, July 9, 2009; available online at http://phx.corporate-ir.net/phoenix.zhtml?c=101911&p=irol-news

Destruction of samples stored for possible medical research ends lawsuit against state.

By Mary Ann Roser

AMERICAN-STATESMAN STAFF

To settle a lawsuit, the state has agreed to destroy more than 5 million blood samples from newborns that it had stored indefinitely for possible research without parents’ consent, the two sides said Tuesday.

The Texas Civil Rights Project filed the lawsuit in U.S. District Court in San Antonio in March on behalf of four parents and a pregnant woman who dropped out later. It claimed that the state’s collection and storage of the samples amounted to “an unlawful search and seizure” and violated the privacy rights of the parents and their children. Under the settlement, the state will destroy 5.3 million samples it has collected between 2002, when the Department of State Health Services began storing the blood, and May 27, when a new state law restricting the practice was signed.

Federal Judge Fred Biery approved the settlement agreement Dec. 14 and gave the state 120 days — until April 13 — to finish destroying the samples, which are stored at Texas A&M University’s School of Rural Public Health.

This year, when stories in the American-Statesman brought the practice to light, the state health department and some medical researchers defended it, saying that collecting the blood spots on paper — done when newborns are screened for various health disorders — might one day provide valuable clues about childhood cancer and other diseases. They said that because the samples were coded and did not identify the babies by name, privacy rights were protected.

But the Texas Legislature approved a law in May requiring medical professionals to inform parents or guardians that the blood spots would be collected and stored indefinitely and could be used for research. Parents who objected could send a statement to the state health department, and their child’s samples would have to be destroyed within 60 days. If the parents didn’t do that, the child could upon reaching adulthood.

Between the time the law passed and Nov. 2, about 6,900 Texans have signed forms asking that the state destroy their child’s samples, out of 240,000 children born in that period, department spokeswoman Allison Lowery said. The department is getting 500 to 600 requests a week to destroy samples, she said.

A statement from the state health department said it “believes settling this lawsuit is in the best interest of this program’s core mission to screen all newborn babies in Texas for life-threatening disorders. Newborn screening saves children’s lives, and settling this lawsuit allows us to continue operating this critical program.”

Jim Harrington , director of the nonprofit civil rights group in Austin, said his organization was “very pleased with the way it worked out.”

Harrington said there were only two options to end the lawsuit: destroy the samples or try and go back to 2002 and get consent from all parents. About 400,000 babies a year are born in Texas.

Among the parents who sued was Austin lawyer Andrea Beleno, Harrington’s daughter-in-law. Her son Joaquin Harrington was born in November 2008, and Beleno said she had no idea “in the haze after giving birth” that any blood had been drawn and stored.

“To me, this whole thing was about consent,” she said. “If they had asked me … I probably would have consented. The fact that it was a secret program really made me so suspicious of the true motives, there’s no way I would consent now.”

Harrington said he will work with a legislative committee before the next regular session in 2011 to refine the new law.

He wants the state to divulge what research it is using the samples for and whether anyone is making money from it. He also wants to see how well the “opt out” provision is working.

Many other states do what Texas had been doing, and a consumer group in Minnesota has been fighting the practice there for several years.

“The State of Texas has taken first steps to restoring the genetic privacy rights of Texas children. This is a wonderful Christmas present for Texas citizens,” Twila Brase, president of the Citizens’ Council on Health Care in St. Paul/Minneapolis, said in a statement.

maroser@statesman.com; 445-3619

An Israeli researcher finds that the device that blasts kidney stones with shockwaves appears to have a restorative effect on the blood vessels of the penis.

By Karin Kloosterman

Treating impotence: Dr. Yoram Vardi, head of the Neuro-Urology Department of Ramban Medical Center

For the 35 million men in America alone who suffer from impotence, the issue of erectile dysfunction is no joke. Wonder drugs like Viagra and Cialis have rejuvenated many a couple’s sex life, but not without the associated risks of heart attack and adversely affected vision.

New research from Israel presented to the European Society of Sexual Medicine in Lyon, France in November suggests that a “shocking” new therapy might work to reinvigorate the male sexual organ in a very safe and effective manner. So far, the benefits of the treatment appear to be long lasting.

Dr. Yoram Vardi, head of the Neuro-Urology Department at the Ramban Medical center in Haifa, Israel, has found that the same device that uses shockwaves to blast kidney stones appears to have a restorative effect on the blood vessels of the penis.

In an initial study of 20 middle-aged men with erectile dysfunction – an inability to maintain an erection – for more than three years, researchers conducted a series of treatments that comprised three weeks of shockwave therapy administered in two 20-minute sessions each week.

No pain, all gain

The patients were allowed to rest for three weeks and then an additional course of low-dose shockwave treatments, with about 100 bars of pressure per shockwave, was administered over another three-week period, using a device that resembles a computer mouse.

Vardi found mostly consistent results in all 15 of the 20 men who benefited from the therapy. All the men noted a return of erectile functioning around the seven-week mark, and a six-month follow-up found that for 13 of the men, the effects were long lasting, while two will require additional treatments.

“There was no pain or additional side effects within six months,” Vardi tells ISRAEL21c. “There was an improvement [in erectile function]. A huge improvement.”

How does he explain it? “We feel the effect is something biological,” says Vardi, suggesting that the treatment encourages blood vessel growth, as found in animal studies. The research team is now in the midst of a new series of tests, which will measure any placebo effect.

“We have done 20 patients more and after a few months the results are approximately the same,” the doctor relates, stressing that such a treatment wouldn’t work on men with muscle or nerve problems, but on those whose erectile problem stems from reduced blood flow.

Shock waves grow blood vessels, treat pain

While commercializing the procedure could be a possibility, Vardi wants to concentrate on the science. But as a researcher and physician with decades of experience, he states, “… I have no question that there is something real in [this new therapy] and that it is important.”

This is the first time that low-dose shockwaves have been used to treat erectile dysfunction, although some research indicates that the treatment could also be useful for growing new blood vessels for the heart. The device is used with higher levels of shockwaves to treat shoulder pain in orthopedics patients. The idea of using sound waves to treat erectile dysfunction came to Vardi when he learned that shockwaves were used to treat men with a curvature of the penis known as Peyronie’s disease.

It’s hard to say when a device might be available to the general public, says Vardi, adding that, “First of all we want to test it more and understand better how effective it can be and how long the [effects of] treatment lasts.” Also, while many men currently self-medicate their erectile disorder, the new shock treatment would require medical consultation and would have to be administered by a physician.

Vardi hopes that in the long run the shockwave therapy could be used to diagnose heart disease at an early stage. Since erectile dysfunction appears in the early stages of diabetes, hypertension and heart disease, a flaccid penis could be a red flag indicating a more grave life-threatening disorder.