A company is preparing human trials of a DNA-based, universal influenza vaccine

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MIT Technology Review, September 23, 2009, by Lauren Gravitz  —  The first doses of H1N1 flu (swine flu) vaccine are due to be shipped to hospitals around the country in the next few weeks–seven months after the virus strain was first identified. These vaccine doses will use either inactivated or weakened live viruses to prompt immunity–an approach that can fail if any of the live viruses is strong enough to replicate, or if the inactivated viruses have been killed beyond all immune recognition.

One biomed company is working to completely revolutionize how vaccines are produced and applied. As Inovio CEO Joseph Kim will describe at the EmTech@MIT 2009 conference on Wednesday, the group is developing a vaccination that could someday protect against all flu strains simultaneously– including avian and swine flu–in one shot. The first human trials are set to begin next year.

The flu virus manages to temporarily evade our immune systems year after year because it mutates so quickly. To fight off the most virulent strains as they emerge, researchers have to change the vaccine every year. Today, most influenza vaccines are grown in chicken eggs, a process that takes six months or more, and they only protect against a few strains of flu–whichever ones experts believe will be circulating during the next flu season.

Inovio hopes to swap this arduous process for one that involves a DNA-based vaccine. With this approach, small bits of DNA that are found in every human flu virus are engineered to be taken up by cells, thereby prompting the cells to produce antibodies against different strains of viral invaders in order to marshal the appropriate immune response.

“We felt it was time for a change. Having to guess at which strains to protect society against for the coming fall is a very antiquated system, with very small room for error,” says Kim, who is also a 2002 TR35 Young Innovator. “We don’t accept that for any other vaccine protocol. You don’t change the measles-mumps-rubella vaccine every year.”

DNA vaccines can be quickly modified, are cheap to produce, and have a much longer shelf life than traditional vaccines. But they suffer from one large drawback: typical injections result in very little DNA being taken up by cells. Inovio is working on that problem by combining vaccines with a technique called electroporation, which delivers a tiny electric shock right after injection. The shock momentarily disrupts cell membranes and enhances DNA uptake.

To create the DNA vaccines, Inovio uses a platform it calls SynCon–short for “synthetic construct.” Using genetic data and complex algorithms, the company has developed a process for designing consensus genes–synthetic ones that look similar enough to components from a variety of viruses, eliciting an immune response broad enough to fight off different strains of the same disease. Inovio’s system identifies the amino acids that are most often present in each position of a few of the virus’s most important genes, then strings these together to create an antigen that induces immunity to a virus with any of these genes.

“To me, it’s a wonderful advance,” says Tom Edgington, an immunologist and professor emeritus at Scripps Research Institute in San Diego. “With DNA vaccines, there is no issue about having a live particle in there anywhere. You can make very large amounts of DNA and keep it for years, and you don’t have to infect a half-million eggs every year.”

The H in H1N1 stands for hemagglutinin, the virus’s outer protein and one that human immune systems respond to. There are 15 known versions of the protein, only five of which are specific to human disease. So by targeting these hemagglutinin proteins, Inovio’s system should, at least in theory, be effective not just for seasonal flu, but for avian (H5N1) and swine (H1N1) flu as well. “There’s nothing magical about swine H1N1 versus seasonal flu,” Kim says. “It’s just a divergence from what your body has been exposed to, and looks different enough to the immune system to evade it.”

In animal tests, this certainly seems to be the case. The company has tested the H1 component of the vaccine in mice infected with the virulent, epidemic-causing 1918 version of the H1N1 virus. The vaccine prevented any visible symptoms in inoculated mice, while every single one of the nonvaccinated mice died.

Of course, putting something as novel as an electroporation vaccine into widespread use could prove difficult especially because it requires its own technology, which is currently expensive. “If you have to do electroporation, that could potentially be a difficult thing to implement, certainly more difficult than spraying something up someone’s nose,” says Greg Poland, director of the Mayo Clinic’s Vaccine Research Group, in Rochester, MN. (This is how live, weakened-virus flu vaccines are currently administered; inactivated-virus vaccines are given with the classic needle and syringe.)

As far as the vaccine itself goes, most of the experts are in agreement. “The idea is a very good one, the need is a great one, and any company that would make a dent into this would certainly be a winner,” says virologist Peter Palese, head of the microbiology department at Mount Sinai School of Medicine, in New York City. But, although the company’s animal studies are an improvement over earlier DNA vaccination results, he notes that “the proof of the pudding will lie in human trials.”

Inovio has tested its H1 and H5 components in animals, and the group hopes to start human trials of the H5 component in early 2010. H1 tests, they believe, are just a short distance behind. “We think it would likely take two shots, a month apart, and then a booster every five years,” Kim says.

Inovio isn’t limiting itself to influenza, either. It has an HIV vaccine in development and is also working to create vaccines for diseases that are of greater concern in developing countries: malaria and dengue are at the top of the list. In contrast to the $20 billion flu-vaccine market, though, “such vaccines hold promise but will never even start to pay for themselves,” says Scripps’s Tom Edgington. “It’s a long path to something that helps the public and changes the world.”

NexBio(R) Presents DAS181 (Fludase(R)*) Potently Inhibits Novel Swine-Origin A(H1N1) and NAI-Resistant Influenza Viruses, at ICAAC 2009

SAN DIEGO, Sept. 15 /PRNewswire/ — NexBio, Inc. announced today the
presentation of two studies of DAS181 activity against H1N1 influenza and
NAI-resistant influenza at the 2009 Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC) meeting on Sunday, September 13, 2009, in San
Francisco, CA.  The work was performed in collaboration with researchers at
the Centers for Disease Control and Prevention (CDC), University of Hong Kong,
and Saint Louis University.

DAS181 (Fludase(R)) is an investigational broad spectrum drug candidate being
evaluated in human clinical development for treatment and prevention of
Influenza-Like Illness caused by all strains of influenza and parainfluenza.
Unlike neuraminidase inhibitors (NAI), e.g. Tamiflu(R), which directly target
the influenza virus (“pathogen target”), DAS181 works by inactivating the
human receptor (“host target”) for these viruses; thus, it may be less likely
to encounter acquired resistance compared with currently-available antiviral
drugs. Extensive, prolonged nonclinical influenza studies have not shown the
development of any meaningful resistance. This approach may have advantages
over mono-therapy or combination therapy which directly target the pathogen.
Previously announced preclinical studies conducted in collaboration with the
CDC and others have shown DAS181 to have significant therapeutic and
prophylactic activity in in vivo animal models and in human ex vivo lung
tissue for a highly virulent H5N1 (A/VN/1203/04) strain of influenza.

A “Late Breaker” presentation, entitled “Novel Swine-Origin A (H1N1) Influenza
Viruses are Potently Inhibited by DAS181, a Sialidase Fusion Protein” examined
in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181
against multiple human novel 2009 influenza A/H1N1 viruses (Novel H1N1 or
“Swine Flu”).  The data presented at the meeting suggested that DAS181
exhibited potent inhibitory activity against these Novel H1N1 viruses in these
different models. 

The related presentation, entitled “In Vivo and In Vitro Activity of DAS181
Against NAI-Resistant Influenza Virus” examined the in vivo and in vitro
activity of DAS181 against patient isolates of community-acquired seasonal
influenza from the 2008-2009 influenza season.  All isolates had the H274Y
mutation associated with resistance to Tamiflu.  DAS181 in vitro was an
effective inhibitor of Tamiflu-resistant influenza virus.  In addition, in
vivo mouse challenge studies with another NAI-resistant strain demonstrated
strong sensitivity to DAS181 treatment.

Both studies are presented by Ronald Moss M.D., Executive Vice President,
Clinical Development and Medical Affairs.  “Based on these encouraging data we
are moving forward with our ongoing clinical development of DAS181, and we
will continue to work closely with FDA, CDC, and NIH on this clinical program
during the current pandemic,” stated Dr. Moss. “Because of viral evolution,
alternatives to current treatment strategies are needed to deal with potential
drug resistance. DAS181 may play an important role for public health
preparedness during influenza pandemics.”

ABOUT NEXBIO

NexBio, Inc. is a privately held clinical-stage biopharmaceutical company
located in San Diego. NexBio’s mission is to save lives and to improve the
quality of life by creating and commercializing novel, broad-spectrum
biopharmaceuticals to prevent and treat current and emerging life-threatening
diseases. DAS181 (Fludase(R)), a recombinant fusion protein, inactivates viral
receptors on the cells of the human respiratory tract, thereby preventing and
treating infection by influenza, including potential pandemic strains, and by
parainfluenza viruses (which may cause serious respiratory illness similar to
influenza and for which there is no approved vaccine or therapeutic).  The
DAS181 development program is funded by the National Institute of Allergy and
Infectious Diseases (NIAID), part of the National Institutes of Health, under
BAA Contract HHSN266200600015C and grant U01-AI070281. ViradinTM, invented and
developed by NexBio, is a parenteral protein under development, currently at
lead optimization stage, directed to the treatment of viral hemorrhagic fevers
and bacterial biothreat sepsis.  TOSAPTM is a technology invented and
developed by NexBio and is used to formulate DAS181 for inhalation, as well as
to make nano/microparticles from virtually any type of molecule.  TOSAPTM is
offered for the formulation of compounds of partners, under license.

For more information about NexBio, Inc., please visit http://www.nexbio.com

* FDA has yet to approve the name Fludase.

DISCLOSURE NOTICE:
This release contains forward-looking information about the research and
development program of NexBio and the potential efficacy of product candidates
that might result from programs that involve substantial risks and
uncertainties. Such risks and uncertainties include, among other things, the
uncertainties inherent in research and development activities; decisions by
regulatory authorities regarding whether and when to permit the clinical
investigation of or approve any drug applications that may result from the
programs as well as their decisions regarding labeling and other matters that
could affect the commercial potential of product candidates that may result
from the program; and competitive developments

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Many bacteria produce various D-amino acids (the mirror images of the more common L-amino acids) to govern the chemistry of their cell walls. The illustration shows the mirror image forms of L- and D-methionine with Vibrio cholerae, the cause of cholera. 

Howard Hughes Medical Institute, September 22, 2009, by Matthew K. Waldor MD, PhD  —   The insides of cells are swimming with amino acids, essential chemical building blocks of life. But flip one of these molecules around, so that it is a mirror image of its former self, and the cell will take notice. New research from Howard Hughes Medical Institute (HHMI) scientists indicates that in the overwhelmingly “left-handed” world of amino acids, the “right-handed” versions of a few of these molecules act as signals that can spur bacteria to adapt to changing environmental conditions.

Amino acids are best known as the building blocks of proteins, which themselves form the biological machinery of all cells. The 20 amino acids that make up proteins each consist of four clusters of atoms branching out from a central carbon atom, like fingers around a palm. These chemical side chains can be arranged clockwise or counterclockwise-orientations chemists call “D” and “L.” Just like left and right hands, a D-amino acid has precisely the same “fingers” as its L counterpart, but is a mirror image.

This difference is biologically crucial, since amino acids interact with molecules that are very sensitive and can recognize only one of the two orientations. In the biological world, this is almost always the L form. No one knows for sure why D-amino acids are scarce, but one possibility is that a chance occurrence established this orientation bias billions of years ago, in the common ancestor of modern life.

HHMI investigator Matthew Waldor and his colleagues found that certain bacteria convert specific amino acids to their D forms when it is time to slow growth. When these D-amino acids are released into the environment, they change the way nearby bacteria construct their cell walls. Waldor and his colleagues published their findings in the September 18, 2009, issue of the journal Science.

Waldor’s lab at Brigham and Women’s Hospital studies microorganisms that cause disease in the human gastrointestinal tract. Nearly all such bacteria, including those that cause cholera, Vibrio cholerae, are shaped like bent rods. Curious whether this common shape has anything to do with the microbes’ virulence, Waldor’s team had been looking for gene mutations that would cause these bacteria to assume a different shape. Eventually, they succeeded when they found that bacteria carrying a mutation in a gene called mrcA had both rod-shaped and spherical forms.

Vibrio cholerae begins life with a period of exponential growth, then stops growing and becomes stationary before dividing again. The mutant cholera strain the group had stumbled upon looked like normal, bent-rod cholera during its exponential growth phase, but became spherical in the stationary phase. Waldor and his colleagues were surprised to discover that the bacteria appeared to be releasing some substance into their own environment that triggered this shape change.

Bacteria are protected by a cell wall made of a strong, elastic polymer called peptidoglycan which determines a bacterium’s shape. Inserting additional polymer elements allows a cell to expand, and conversely, when a cell stops growing, it can slow peptidoglycan synthesis to conserve resources. According to Waldor, researchers had long been puzzled as to how peptidoglycan production and assembly were regulated, because these processes take place in a space external to the inner membranes, away from the main compartment of the cell – the cytoplasm – where nearly all regulatory factors reside.

When the team realized their morphing cholera mutant might hold clues to how peptidoglycan synthesis is regulated, they refocused their research and set out to identify the factor triggering the shape change. They began by taking a closer look at the type of molecules floating in the cells’ culture medium, and discovered the presence of some unusual amino acids: the D forms of the amino acids methionine and leucine.

They found that cholera bacteria use an enzyme called a racemase to create large quantities of D-methionine and D-leucine from their L counterparts. The racemase inhabits the cell’s periplasmic space between the inner and outer membranes, and begins synthesizing D-amino acids when the cell stops growing, the team found. The D-amino acids then alert the cell’s wall-building proteins to slow their production of peptidoglycan, as demand has waned.

The team constructed a mutant that does not produce the racemase, and therefore could not manufacture the D-amino acids. So when they stopped growing, their walls continued to expand. They contained more — but weaker — peptidoglycan chains that left the cells 20 times more likely to rupture than normal rod-shaped cells. Waldor says this indicates that D-amino acids serve as a check on peptidoglycan production. “Our work suggests this is a new fundamental [regulatory] mechanism,” he says.

The importance of D-amino acids doesn’t end there, adds Hubert Lam, a co-author and postdoctoral researcher in Waldor’s lab. After examining the cholera bacteria, the team looked for the actions of D-amino acids in other species. They turned to Bacillus subtilis, a commonly studied bacteria that is far from V. cholerae on the evolutionary tree. They found evidence that the presence of D-amino acids reduced peptidoglycan production in B. subtilis, as well. They speculate that D-amino acids may act as a signaling molecule between individual B. subtilis cells in a population.

“D-amino acids appear to be produced when bacteria are with other bacteria,” says Lam. Adding the D-amino acids to cultures of growing B. subtilis appeared to stop growth of their cell walls, suggesting that the molecules may serve as a sort of brake for population growth. As a population expands, bacteria may release D-amino acids essentially to let one another know they are there, and the population as a whole should slow growth to avoid consuming limited resources too quickly.

The team says there is still much to be learned. While it’s clear that D-amino acids affect the structure of the cell wall, the molecular mechanisms involved have yet to be worked out. In addition, there is a lot to be learned about amino acids’ potential role in signaling between individuals – or even between different species. According to Lam, “the sheer amount of D-amino acids being produced is very unexpected.” Producing so much of anything takes a lot of energy, and so evolutionarily, it must be important, he says. 

About Matthew K. Waldor, M.D., Ph.D, HHMI Investigator

 Brigham and Women’s Hospital

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Dr. Waldor is also Professor of Medicine and Microbiology at Harvard Medical School and an attending physician in infectious diseases at Brigham and Women’s Hospital, Boston. As an undergraduate at Yale University, he studied philosophy and biology. He carried out his doctoral work with Larry Steinman and received his M.D. and Ph.D. degrees from Stanford University. After an internal medicine residency at Brigham and Women’s Hospital and an infectious disease fellowship at Massachusetts General Hospital, he did postdoctoral research with John Mekalanos at Harvard University.

Matthew Waldor studies the evolution, cell biology, and pathogenicity of enteric bacteria that cause human disease.

For the full story, go to:  http://www.hhmi.org/news/waldor20090918.html

By Darrell G. Kirch and Edward D. Miller

WashingtonPost.com, September 22, 2009  —  Whatever version of health-care reform emerges, the legislation needs to address two problems with the health-care system: uncoordinated care among physicians, hospitals, and other providers; and a payment system that encourages often unnecessary care. Those of us on health-care’s front lines think that these problems can be addressed effectively in “Health-care Innovation Zones” (HIZ’s), proposed by Rep. Allyson Schwartz (D-Penn.) in a new bill.

In a Health-care Innovation Zone, a regional alliance consisting of an academic medical center, local hospitals, physicians and other health-care organizations coordinates and delivers the full spectrum of care in ways that reward quality. These Innovation Zones could also test new, more patient-centered models of care, such as the medical home and “accountable care organizations,” as well as new payment models that have the potential to vastly improve care and reduce costs.

At Johns Hopkins Medicine, one of the nation’s leading academic medical centers, the much-talked about theory of such new care and payment models is already being tested. The JHM alliance serves a large group of over 135,000 economically, medically and socially challenged Medicaid patients as well as close to 30,000 military beneficiaries and their families. Through a network of owned and contracted providers located across Maryland, and using tools such as predictive modeling, JHM has reduced expenditures for patients with highly complex medical needs and a history of substance abuse; reduced the total costs of caring for our patients with end-stage renal disease by 47 percent; exceeded national benchmarks on all measures of clinical quality for our dialysis population; reduced the odds of hospital admissions for patients at the end of life; and earned high patient satisfaction ratings across the state. Indeed, our member satisfaction for our military health plan is in the 98th percentile.

We believe that other academic medical centers, using all the tools that could be applied within a Health-care Innovation Zone, could achieve the same outcomes. Many academic medical centers already have aligned networks of faculty physicians and teaching hospitals. They already provide the full range of health services, from preventive care to the most complex. They already have cutting-edge technology and strong investments in health information technology. They already provide a disproportionate share of vital urban health services and nearly half of the nation’s hospital-based charity care. And because they work in partnership with one another, they can share what works — and what doesn’t work. In short, academic medical centers should serve as the anchors of Health-care Innovation Zones and contributors to the rational redesign of our health care system.

Darrell G. Kirch is president and CEO of the Association of American Medical Colleges. Edward D. Miller is dean of the medical faculty and CEO of Johns Hopkins Medicine.

FierceBiotech.com, September 22, 2009  —  The Wall Street Journal assesses the race among three biotechs to develop a blockbuster new obesity drug. Arena Pharmaceuticals [1] and Vivus [2] are on track to file for an approval by the end of this year, with Orexigen Therapeutics [3] slated to follow soon after. And the Journal gives the lead to Vivus’ Qnexa, which has hit two key endpoints laid down by the FDA for an approval. 

Regulators in the U.S. have a clear set of benchmarks for an obesity approval. The FDA wants to see at least a third of trial participants lose at least five percent of their body weight, with the tally at least double that of the placebo arm. Or they ask for average weight loss that’s five percentage points ahead of the control arm. Then there are special conditions. Arena’s lorcaserin, for example, has sailed through trials with minimal side effects. And Orexigen, a developer manned at the top by a group of veterans [4] from Amgen and big pharma companies, added an antidepressant to their drug that could make it more effective for a subset of patients. 

The stakes are high. Analysts note to the WS Journal that one percent of the market is worth a blockbuster billion dollars. And that means that just getting an approval is a big deal, no matter whether the developer wins, places or shows in this race.

GoogleNews.com, September 22, 2009, by Tracy Staton  —  Teva Pharmaceutical Industries proves that the drug industry is an equal-opportunity job-cutter. It’s not just the purveyors of branded meds like Merck, Schering-Plough, Wyeth, Pfizer, Sanofi-Aventis, and Roche that are scaling back their payrolls, either in the wake of mergers or as part of companywide restructurings. Even the generics makers who pose a competitive threat to Big Pharma are having to rejig their operations these days. 

The latest: Teva will shut down one of its Czech Republic factories by the end of this year, Reuters reports, shedding 400 jobs in the process. That’s on top of the 315 jobs Teva is relocating from the higher-cost labor market of Ireland to a lower-cost plant in either eastern Europe or Israel.

Some of the 400 lost Czech jobs will return, once Teva has ploughed a planned $58 million into boosting production at its main plant in the country. That expansion will end up creating 300 new positions, the company says. Currently, Teva employs 1,700 in Czech Republic.