**BIOTECH AND PHARMA NEWS**

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Clinic Roundup/BIOWORLD Today


Aradigm Corp., of Hayward, Calif., said it initiated a Phase II trial of its inhaled liposomal ciprofloxacin, which has been granted orphan drug designation in noncystic fibrosis bronchiectasis in adults. Following an antibiotic wash-out period, 36 patients will be enrolled to receive daily inhaled liposomal ciprofloxacin for 28 consecutive days. The primary endpoint will be the change in the density of Pseudomonas aeruginosa bacterial colony forming units in the sputum over the treatment period. Secondary endpoints will include pulmonary function measurements and respiratory symptoms.

Bavarian Nordic A/S, of Kvistgard, Denmark, said its cancer research unit, BN ImmunoTherapeutics, completed an interim analysis of its first two studies of MVA-BN-HER2 cancer vaccine immunotherapy in breast cancer patients. With 27 of 30 patients vaccinated, no drug-related severe adverse events had been reported, and the vaccine has been shown to be well tolerated and immunogenic. Immune evaluation of samples from 18 patients revealed that 12 had developed immune response. Final data are expected around late 2008 or early 2009.

********************basis Therapeutics Inc., of La Jolla, Calif., said results of its 14-day Phase Ib trial in subjects with mild hypercholesterolemia showed that MB07811 was safe and well tolerated across the seven doses tested, which ranged from 0.25 mg to 40 mg. No differences in heart rate, heart rhythm or blood pressure were observed between the MB07811 and placebo arms. Mild increases in liver enzymes were observed at the higher doses of MB07811, along with dose-related mean shifts in thyroid hormone levels.

OSI Pharmaceuticals Inc., of Melville, N.Y., said it initiated the first-in-human study of its development compound PSN602, an oral dual serotonin and norepinephrine reuptake inhibitor and 5-HT1A agonist developed for the treatment of obesity. The study is designed to provide preliminary information on the safety, tolerability and pharmacokinetics of PSN602 in healthy lean and overweight/obese subjects, as well as on the effects of PSN602 on appetite and food intake in healthy overweight/obese subjects.

Sepracor Inc., of Marlborough, Mass., said Phase III results of eslicarbazepine acetate (SEP-0002093) in epilepsy patients demonstrated a significant reduction in the frequency of partial seizures in those who received the drug in combination with existing antiepileptic therapies. Eslicarbazepine acetate once-daily at doses of 800 mg and 1,200 mg significantly reduced seizure frequency over each 12-week maintenance period vs. placebo, and patients treated with the drug demonstrated sustained reduction in seizures over an open-label, one-year period. Results from those studies, presented at the Eilat Conference on New Anti-Epileptic Drugs in Sitges, Spain, are expected to be included in Sepracor's new drug application, targeted for late 2008 or early 2009.

Speedel Holding Ltd., of Basel, Switzerland, said results from a Phase IIa proof-of-concept trial of SPP635, a next-generation renin inhibitor, demonstrated strong efficacy and good safety. Based on those results, Speedel said it is continuing Phase IIa development in a special population of diabetic patients with mild to moderate hypertension. Data were presented at the International Society of Hypertension meeting in Berlin. The company also reported several preclinical posters, including data from a rat study showing that SPP301, an endothelin receptor A antagonist, might cause leakage of fluid from the intravascular into the extravascular space, suggesting a lower dose of the compound could be effective against diabetic nephropathy while avoiding fluid retention and edema.

Suven Life Sciences Ltd., of Hyderabad, India, started a Phase I program of SUVN-502, an orally active antagonist of 5-HT6 receptor in development for Alzheimer's disease, attention deficient hyperactivity disorder, Parkinson's disease and schizophrenia. The objective of the study is to assess safety and bioavailability of SUVN-502. The single-ascending dose studies are expected to be completed by September, and the multiple-ascending dose studies will be conducted afterward.

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Other News To Note/BIOWORLD Today

Aastrom Biosciences Inc., of Ann Arbor, Mich., said it received notice from Nasdaq that it had not regained compliance with the minimum closing bid price, pursuant to a deficiency letter dated Dec. 20, 2007. Because the company met all inclusion criteria, except for the minimum bid price, the company has an additional 180 calendar days, or until Dec. 15, to regain compliance.

Ambrilia Biopharma Inc., of Montreal, said it demonstrated and validated in vivo proof of concept with its NGR-delivery technology applied to a carrier containing a small interfering RNA. Data in animal tumor models showed efficient siRNA delivery to the tumor tissue, internalization and suppression of a cancer-promoting gene. With those data in hand, Ambrilia said it intends to intensify its divestment efforts for that technology.

Artecel Inc., of Sunnyvale, Calif., said litigation concerning the composition-of-matter patent covering stem cells isolated from adipose tissue was decided in favor of Artecel's licensor, the University of Pittsburgh, and against the University of California, which licensed intellectual property rights to San Diego-based Cytori Therapeutics Inc. Cytori said the patent does not affect commercialization of its Celution System or its product pipeline, though the company maintained that the court's decision was incorrect. The University of California could elect to appeal the ruling.

Bone Medical Ltd., of Bentley, Australia, said it reached an initial agreement granting Seoul, South Korea-based Hyundai Pharmaceutical Co. Ltd. a license to sell Bone's CaPTHymone, an oral parathyroid hormone osteoporosis product, in South Korea. Under the terms, Bone Medical will qualify for an up-front payment, milestone payments related to product development, approval and launch, as well as payments for the supply of bulk product. Bone also will be eligible for royalties. Specific financial details were not disclosed.

Discovery Laboratories Inc., of Warrington, Pa., said it anticipates submitting a formal response to the FDA approvable letter for Surfaxin in September, after a meeting with the agency provided clarification on outstanding issues. The company received its third approvable letter in May for Surfaxin in premature infants with respiratory distress syndrome. The recent communication with the FDA indicated that two items still need to be addressed, requesting additional Surfaxin biological activity test data and asking the firm to justify the proposed specifications for certain lipid-related impurities in the individual active pharmaceutical ingredients that comprise Surfaxin. Discovery Labs said its response to the approvable letter could be deemed a Class 1 submission, which would give the application a target review period of 60 days. Analyst Jonathan Aschoff, of Brean Murray Carret & Co., wrote in a research note that the drug is "worthy of approval," and that the company could "assemble a sales force swiftly in as little as two or three months, which could allow initial Surfaxin sales" in the first quarter of 2009. News of the three-month delay, however, sent company shares (NASDAQSCO) falling 21.3 percent to close Thursday at $1.70, down 46 cents. (See BioWorld Today, May 5, 2008.)

Eurand NV, of Philadelphia, received an approvable letter for EUR-1008 (pancrealipase capsules) in exocrine pancreatic insufficiency. The company said the letter does not require any additional clinical studies prior to the product gaining approval. Eurand is working with the agency to provide a response to outstanding issues and, based on current information, still anticipates launching EUR-1008 in the second half of this year.

ImmunoCellular Therapeutics Ltd., of Los Angeles, signed a research agreement with George Mason University in Fairfax, Va., for the development of a blood test to detect small-cell lung cancer and pancreatic cancer using IMUC's monoclonal antibody technology. The test would be designed to look for certain cancer markers, potentially allowing for early detection and for assisting the selection of patients most likely to respond to the company's antibody therapy, ICT-109.

Invitrogen Corp., of Carlsbad, Calif., signed a non-binding letter of intent with the International Regulome Consortium in Ottawa, Ontario, to develop tools for stem cell research that will aid in the development of new therapies. Invitrogen will contribute services and technology to help IRC researchers map the genetic circuit board that regulates the way in which stem cells give rise to specialized cells such as neurons. IRC is a third-generation genome project, involving 58 researchers from 34 institutions worldwide.

Meridian Bioscience Inc., of Cincinnati, completed the purchase of technology and products, including infectious disease recombinant proteins and cardiac antigens from Ithaca, N.Y.-based Vybion Inc. in exchange for an undisclosed cash payment and future royalties based on sales of applicable products. The deal is expected to allow Vybion to focus on other activities, including CoMab, a preclinical monoclonal antibody in development for cocaine abuse.

Resverlogix Corp., of Calgary, Alberta, is collaborating with the Cleveland Clinic to develop a protocol for RVX-208, a small molecule designed to enhance the production of ApoA-1 and functional high-density lipoprotein, in a Phase IIb intravascular ultrasound (IVUS) study. The trial, which will seek to measure the rate of regression of coronary disease using IVUS, is expected to start next year, upon completion of a successful Phase Ib/IIa study.

Spectrum Pharmaceuticals Inc., of Irvine, Calif., formed a Canadian affiliate, Spectrum Pharma Canada Inc., which will have its headquarters in Quebec. The firm gained Canadian approval earlier this year to start clinical trials of EOquin, in development for noninvasive bladder cancer.

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New Weapon For Attacking Tumor Invasion And me.tastasis




A team led by Dr. Ji-Kun Li has determined that AMD3100, originally developed in acquired immune deficiency syndrome treatment, could markedly inhibit spreading of colorectal cancer cells by blocking a new pair of ligands and its unique receptor. This effect differs from the usual inhibition by a conventional chemotherapic agent that is more specific to cancer cells with high me.tastatic potential.


In vitro, AMD3100 has shown a significantly inhibitory effect on invasion and migration in colorectal cancer cell line. This effect can be further enhanced at higher concentration. This study was performed by a team led by Professor Ji-Kun Li from the Shanghai Jiao Tong University.

Colorectal cancer (CRC) is one of the main causes of cancer-related death in the world. The mortality of CRC is principally attributed to the development of liver and other me.tastases.
It may be helpful for doctors to find a new biomarker that predicts early recurrence or distant organ me.tastasis.
There is also a pressing need for more effective treatments for patients with advanced colorectal cancer.

In the view of the authors, their research has shown elevated CXCR4 (a new receptor on cancer cells) expression in primary CRC is associated with liver and lymph node me.tastasis, which prompts them to elucidate the mechanism of this phenomenon. They also found AMD3100 had significant antitumor activity through regulating pathways downstream of CXCR4 and impaired formation of tumor micro vessels and expression of invasive associated genes.

Inhibition of CRC cells survival and me.tastatic spread by interfering with the ligand- receptor axis has been successful in vitro. Though these data do not necessarily predict a satisfactory outcome of clinical trials, they provide a novel strategy based on this new molecule pair.

Journal reference:

Li et al. Inhibition of CXCR4 activity with AMD3100 decreases invasion of human colorectal cancer cells in vitro. World Journal of Gastroenterology, 2008; 14 (15): 2308 DOI: 10.3748/wjg.14.2308

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Lou Gehrig's Protein Found Throughout Brain, Suggesting Effects Beyond Motor Neurons

http://www.sciencedaily.com/releases...0616144848.htm

two years ago researchers at the University of Pennsylvania School of Medicine discovered that misfolded proteins called TDP-43 accumulated in the motor areas of the brains of patients with amyotropic lateral sclerosis (ALS), or Lou Gehrig's disease. Now, the same group has shown that TDP-43 accumulates throughout the brain, suggesting ALS has broader neurological effects than previously appreciated and treatments need to take into account more than motor neuron areas.

"The primary implication for ALS patients is that we have identified a molecular target for new therapies," says co-author John Q. Trojanowski, MD, PhD, Director of Penn's Institute on Aging. "The other implication is that new therapies for ALS now need to go beyond treating only motor neurons."

Traditionally, ALS has been diagnosed based on muscle weakness and neurodegeneration of the upper and lower motor neurons that extend from the motor cortex to the spinal cord and brainstem motor neurons, which directly innervate voluntary muscles. For example, if you want to wiggle your big toe, the signal travels from the motor neuron in the cortex at the top of your head to a synapse on the lower spinal cord motor neurons in the lower back, which, in turn transmit the "wiggle" command by sending a signal to the muscles that move your big toe. Patients with ALS cannot wiggle their big toe or complete other voluntary muscle movements, including those carried out by their other extremities and eventually, by the diaphragm that moves air in and of their lungs.

The study was conducted by examining post-mortem brain tissue of 31 ALS patients. The accumulation of TDP-43 was imaged by detecting TDP-43 with an antibody specific for this protein. TDP-43 pathology was observed not only in the areas of the brain and spinal cord that control voluntary movements, as expected, but also in regions of the brain that involve cognition, executive functioning, memory, and involuntary muscle control. TDP-43 pathology was not observed in any of the controls that did not have ALS.

The pathological TDP-43 observed in ALS brains is different in two ways from normal TDP-43 that is found in most cells. The ALS-associated TDP-43 includes fragments of normal TDP-43 as well as other abnormally modified forms of TDP-43, and it is located in the cytoplasm of neurons; whereas, normal TDP-43 is found almost exclusively in the cell nucleus. In ALS, the pathological TDP-43 accumulates in large "globs," mainly in cell bodies.

"Our observation of TDP-43 in the brains of ALS patients suggests that ALS and two other neurodegenerative diseases called ALS- PLUS [ALS with cognitive impairments] and FTLD [frontotemporal lobar disease] may all have the same underlying molecular pathology involving abnormal TDP-43," says Trojanowski. "This constitutes a paradigm shift in the way we think about these diseases."

Current research is focused on understanding the basic biology of TDP-43 in cell culture systems. The research team is now trying to find out whether pathological TDP-43 causes nerve cells to lose their normal function or if they take on a toxic function. "The over-riding goal that drives our work is helping ALS patients," says Trojanowski.

Felix Geser, of Penn, was lead author on this study. Linda Wong, Maria Martinez-Lage, Lauren Elman, Leo McCluskey, Sharon Xie, and Virginia Lee, all of Penn, and Nicholas Brandmeir, of Albany Medical College, Albany, NY were co-authors. This research was supported by grants from the National Institute on Aging.

An article on this research appeared recently in the Archives of Neurology.

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Legionnaire Microbe's Tricks Discovered

Yale University researchers have shed new light how bacteria
like the ones that cause Legionnaires' disease and Q-fever raise such havoc in human patients.

In order to survive, the gram-negative bacteria use genes that have evolved in tandem with ones in their hosts to essentially disarm immune system cells trying to kill them, the scientists report in the journal Science.

"Because of their life style, trying to identify how these organisms cause disease has been really difficult,'' said Craig Roy, professor at the Yale School of Medicine in the section of microbial pathogenesis.

Roy and his group described one innovative way the organisms inflict their damage with impunity.

Some gram-negative pathogens such as Legionella pneumophila, and Coxiella burnetii, the cause of Q fever, actually secrete proteins into eukaryotic cells, or cells with a nucleus. But exactly what those proteins did was not known.

Legionnaires' disease is a dangerous form of pneumonia often contracted by inhaling water droplets containing the organism. Q-fever in humans can cause high fevers, chills and can also develop into pneumonia. Both often go undiagnosed.

Previous genome scans of the gram-negative bacteria that cause these diseases had identified a high prevalence of genes called Anks, for ankyrin repeat homology domains. These genes fascinated scientists because they appear very similar to numerous genes in eukaryotic cells that regulate a multitude of processes. These bacteria have "borrowed'' or co-evolved genes from their hosts to survive in the cell. In fact, some species of these bacteria cannot exist outside of a eukaryotic cell.

Roy's lab showed that Ank proteins are secreted into immune system cells called macrophages, and once inside, turn off mechanisms within the cell designed to destroy the bacteria.

Roy believes that more such survival tricks of gram-negative pathogens will be found but adds, "this study at least gives us a foothold" for further study.

Because these bacteria tend to behave like viruses and actually invade cells, they might be susceptible to a vaccine that targets specific elements of the Ank protein and allow macrophages to complete the job, he said.

Other authors included Xiaoxiao Pan, Anja Lührmann, Ayano Satoh, Michelle A. Laskowski-Arce of Yale.

The research was supported by a grant from the National Institutes of Health.

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Cells Have An Appetite For Micro-doughnuts

http://www.sciencedaily.com/releases...0624120237.htm

Just like humans, liver cells can’t resist eating just one or two small doughnuts, say chemists from Scotland in the Royal Society of Chemistry journal Chemical Communications.

Exploiting liver cells’ appetite for polystyrene ring “doughnuts”, just a few microns across, might give scientists a new way to deliver drugs selectively, potentially eliminating nasty side effects of life-saving treatments such as chemotherapy.
Mark Bradley and colleagues at the University of Edinburgh, UK, serendipitously made the polymer doughnuts while studying potential drug-carrying microparticles.

While synthesising micro-spheres, the team added a small amount of dioxane to their usual ethanol solvent. To their surprise, the resulting microparticles were regular in size and shape, with a hole through the middle like a doughnut.

“Their unique and highly uniform structure was immediately interesting to us and we considered the possible applications they may have – one of which was as carrier particles for cellular delivery,” said Bradley.

When they tested the uptake of the doughnuts into different types of cells, the team found they had an overwhelming preference for liver cells.

The high cell specificity these doughnuts showed led the team to conduct extensive in vivo testing in rats. The doughnuts were injected into the tail and within four hours they were detected solely in the liver region (yellow in image), with no adverse effects observed in the animal after the experiment.

Bradley believes there are other uses for the micro-doughnuts besides drug delivery, such as filtration or purification devices, but the team will be keen to develop their ability to selectively deliver drugs into cells.

Journal reference:

Lois Alexander et al. Dunking doughnuts into cells—selective cellular translocation and in vivo analysis of polymeric micro-doughnuts. Chemical Communications, 2008; DOI: 10.1039/b805323e

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DNA Knot Keeps Viral Genes Tightly Corked Inside Shell, Scientists Discover

http://www.sciencedaily.com/releases...0617142904.htm

(June 23, 2008) — A novel twist of DNA may keep viral genes tightly wound within a capsule, waiting for ejection into a host, a high-resolution analysis of its structure has revealed.

Using electron microscopy and three-dimensional computer reconstruction, UC San Diego biologists and chemists have produced the most detailed image yet of the protein envelope of an asymmetrical virus and the viral DNA packed within, they report in the journal Structure. The image, with a resolution of less than a nanometer, or a millionth of a millimeter, will help to unravel how the virus locks onto its host and infects the cells by injecting its DNA.

By assembling more than 12,000 microscopic views of frozen viral particles from different angles, UCSD chemists Jinghua Tang, Norman Olson and Timothy Baker, a professor of chemistry and biological sciences, have determined the structure of a bacteriophage called phi29 with a resolution finer than 8 Angstroms (one Angstrom equals a tenth of a nanometer). Their project was part of a long-term collaboration with molecular virologist Dwight Anderson and his colleagues at the University of Minnesota.

Although the structures of spherical viruses with a high degree of symmetry have been resolved using similar methods, many more images were required to accomplish the same task for the head-and-tail shape of phi29. The UCSD scientists said their images of phi29 are twice as fine as those created in previous efforts to visualize viruses with a similar shape.

A comparison between images of the virus with and without its DNA cargo revealed that the DNA twists tightly into a donut shape, or toroid, in the neck of the virus between its head and tail. “This highly distorted DNA structure is unlike anything previously seen or even predicted in a virus,” said Timothy Baker who headed the research team. “It’s an improbably tight turn for DNA, which is generally considered inflexible over very small distances.”

During assembly of the virus, a molecular motor in the neck winds the DNA strand into a tight coil within the head. “It’s under tremendous pressure -- about 20 times that of champagne in a bottle,” said Tang, the lead author of the paper.

The knot-like shape of the toroid, along with interlocking bumps in the protein envelope, may keep the DNA wedged into the capsid until the virus docks onto the host cell.

"It's poised in this tube waiting to go through the bacterial wall," Baker said. "All of the components work together to create an infection machine."

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Certain Anticancer Agents Could Be Harmful To Patients With Heart Disease

http://www.sciencedaily.com/releases...0623175343.htm

(June 25, 2008) — A set of promising new anticancer agents could have unforeseen risks in individuals with heart disease, suggests research at Washington University School of Medicine in St. Louis. The anticancer drugs -- which go by the strange name of hedgehog antagonists -- interfere with a biochemical process that promotes growth in some cancer cells. But the researchers showed that interfering with this biochemical process in mice with heart disease led to further deterioration of cardiac function and ultimately death.

"This finding should serve as a warning that these drugs might have adverse effects on the heart and that it could be very important to monitor patients' cardiovascular health when using this type of anticancer drug," says senior author David Ornitz, M.D., Ph.D., the Alumni Endowed Professor and head of Developmental Biology. The research was reported June 20, 2008, in advance online publication in the Journal of Clinical Investigation.

Hedgehog antagonists are drugs that inhibit the hedgehog signaling pathway, a chain of biochemical signals that regulate cellular growth and differentiation. The odd term hedgehog has little to do with the small, spiny mammals -- it originated when scientists noted the spiky, hedgehog-like appearance of fly embryos with abnormal hedgehog genes. Every organism in the animal kingdom has hedgehog genes, which play an essential role in guiding cells to mature into the appropriate form for proper function.

Ornitz and his research team, including lead author Kory Lavine, M.D., Ph.D., now a resident in the Cardiovascular Division of the Department of Medicine at Washington University School of Medicine, are on the forefront of research into how blood vessels in heart muscle develop in growing embryos. They recently found that the hedgehog signaling pathway was vital to the development of the heart's blood supply.

Now the Washington University research team has demonstrated that the hedgehog signaling process is important not just in the early development of the heart, but also in adult hearts -- to maintain cardiac blood vessels. They found that completely blocking hedgehog signaling in the hearts of adult mice caused many small coronary blood vessels to disappear, leaving heart muscle short of oxygen and leading to heart failure.
In mice with experimentally induced heart attacks, mildly inhibiting hedgehog signaling led to a worsening of their heart conditions.

"We gave mice small amounts of antibodies against hedgehog, and in those that had a recent myocardial infarction (heart attack), this led to poorer heart function and some lethality," explains Lavine. "We've shown that small decreases in the hedgehog pathway in the setting of heart disease can lead to deleterious outcomes, and since a number of patients with cancer also have heart disease, this raises concern for those who might be treated with hedgehog antagonists."

Studies suggest that abnormal activation of the hedgehog pathway is implicated in many different types of cancer, and drugs that impede hedgehog signaling are being tested against several of these cancers, including basal cell carcinoma (a type of skin cancer), prostate cancer, pancreatic cancer, colorectal cancer and medulloblastoma (a type of brain tumor). These trials are still in the early stage.

The current study was the first demonstration that hedgehog signaling is essential to maintain a healthy supply of blood vessels in heart muscle in adult organisms.
"Nobody had ever looked for hedgehog signaling in the adult heart before," says Ornitz. "Kory discovered that the hedgehog signaling pathway is a mechanism to regulate the heart's vasculature by influencing growth factors that promote blood vessel growth. The body can tune the hedgehog pathway to modulate its signal and increase and decrease blood vessels on demand, providing a mechanism to ensure a constant supply of oxygenated blood for the energy-hungry cells of heart muscle."

The researchers say that the role of hedgehog signaling in the vasculature of the heart means that it could be a target for new drugs that could be used to treat heart disease. Ornitz says the study also suggests that hedgehog signaling could be required to maintain blood vessels elsewhere in the body.
That means it could also be uniquely important in the brain, which has a very dense capillary network, and that drugs that increase hedgehog signaling could possibly be useful to treat strokes. Lavine, who has just graduated from the Washington University Medical Scientist Training Program will begin an internal medicine cardiology residency and cardiovascular diseases fellowship. He plans to investigate the contribution of hedgehog signaling in other forms of heart disease such as diabetic cardiovascular disease.

Funding from the National Institutes of Health, the American Heart Association and the Virginia Friedhofer Charitable Trust supported this research.

Journal reference:

Lavine KJ, Kovacs A, Ornitz DM. Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI34561