Archive for January, 2010

Alzheimer’s Study Leads To Better Drug For Infections

Last Updated on Friday, 29 January 2010 10:55 Written by Editor Friday, 29 January 2010 10:55

Research into Alzheimer’s disease seems an unlikely approach to yield a better way to fight urinary tract infections (UTIs), but that’s what scientists at Washington University School of Medicine in St. Louis and elsewhere recently reported.

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks. Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” says senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” says co-lead author Jerome S. Pinkner, laboratory manager for Hultgren. “We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment.”

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks. Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease. When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren says.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he says.

Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, published online.

Funding from the Swedish Natural Science Research Council, the Knut and Alice Wallenberg Foundation, the National Institutes of Health and the Burroughs Wellcome Fund supported this research.

Source
Washington University in St. Louis

Posted under Alzheimer's disease, Press Releases | Comments Off

University of California, San Francisco, Researcher Receives ASBMB-Merck Award

Last Updated on Thursday, 28 January 2010 06:25 Written by Editor Thursday, 28 January 2010 06:25

Bethesda, MD, December 12, 2009 –(PR.com)– James A. Wells, professor and chairman of the department pharmaceutical chemistry at the University of California, San Francisco, and director of UCSF’s small molecule discovery center, has been named the winner of the 2010 American Society for Biochemistry and Molecular Biology-Merck Award for his pioneering studies in the field of protein engineering.

Wells, who also serves on the ASBMB Council, will present an award lecture, titled “Probing and Controlling Cellular Remodeling Enzymes,” at 2:15 p.m. Monday, April 26, at the 2010 annual meeting in Anaheim, Calif.

Wells integrates multiple disciplines, including biophysics, cell biology, chemical biology, molecular biology, enzymology and proteomics, to design small molecules and proteins that can selectively activate or inhibit cellular processes such as differentiation and apoptosis. Through these efforts, Wells hopes to better understand how signaling events drive responses, such as cell growth and death, and perhaps discover new drugs to treat diseases like cancer.

Along the way, Wells has developed numerous innovative methodologies to improve protein engineering, molecular screening and pharmaceutical chemistry, including a disulfide-based protein-trapping technology, substrate-assisted catalysis and N-terminomics.

“[Wells] is an exciting and highly creative scientist,” noted Ian A. Wilson, professor of structural biology at The Scripps Research Institute, “and these methods that he has pioneered have been invaluable to countless researchers in a multitude of fields.”

“His unbridled enthusiasm is infectious and ensures his lab is fully regaled with a plethora of ideas,” Wilson continued, “so they can unleash their individual talents to further progress drug discovery, biochemical mechanisms, protein function and understanding of key cellular events that impact human health.”

Wells’ impressive expertise in protein engineering stems from a long and renowned career in the pharmaceutical industry. Before joining UCSF, Wells spent nearly two decades at Genentech Inc., where he was a founding scientist of its protein engineering department. He later founded and served as president and chief scientific officer of Sunesis Pharmaceuticals and helped invent a novel drug-discovery platform called Tethering, which efficiently screens molecules to identify the most potent compounds that block specific protein action.

Prior to that, Wells received his bachelor’s degree in biochemistry from the University of California, Berkeley, in 1973 and his doctorate in biochemistry from Washington State University in 1979. He also took on postdoctoral fellowships at both Washington State University and the Stanford University School of Medicine before joining Genentech in 1982.
his career, Wells has made enormous contributions to our understanding of enzyme mechanisms, allostery, protein plasticity, protein-protein interfaces, small molecule discovery, hormone receptor signaling, molecular recognition, protease signaling and apoptosis,” said Molecular and Cellular Proteomics co-editor Alma Burlingame, who is also a professor of chemistry and pharmaceutical chemistry at UCSF. “Not only has his science led to fundamental discoveries, it also produced new products in both the industrial enzyme and pharmaceutical sectors.”

The ASBMB-Merck Award, presented annually, recognizes outstanding research contributions in the fields of biochemistry and molecular biology.

Source: pr.com

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Techne accelerates sample concentration

Last Updated on Thursday, 28 January 2010 06:23 Written by Editor Thursday, 28 January 2010 06:23

The Techne Sample Concentrator provides fast solvent or diluent evaporation without sample loss when used with one of the company’s Dri-Block heaters.

The height-adjustable head of the concentrator delivers a flow of inert gas that removes evaporated solvent from the surface of solutions in tubes or 96-well plates.

Traditional methods of reducing the volume of solvent or diluent can take many hours, requiring the use of centrifugation, vacuum, heat and expensive cold traps, while also causing sample loss.

By combining heat from below with a flow of inert gas to the liquid surface, the Techne Sample Concentrator and Dri-Block heater have been shown to provide fast and easy solvent evaporation without loss of sample quality or quantity.

The concentrator features a gas chamber mounted on a fully adjustable stand for accurate height control.

Inert gas, usually nitrogen, is directed onto the sample surface via a set of high-quality stainless-steel needles positioned in a silicon matrix according to the required spacing.

Any sample format can be accommodated, as the concentrator is available in two models: one for 0.2ml micro centrifuge tubes, test tubes, boiling tubes, cuvettes and other small containers; and one for 96-well plates and deep-well storage plates.

The Techne Sample Concentrator is suitable for use in drug screening, hormone assays and chromatographic analysis – as well as in industrial settings where it is important to remove solvents or increase the concentration of samples.

It will be especially useful for both combinatorial chemistry, for which users can concentrate compounds directly in standard 96-well storage plates; and microarrays, which require a high sample concentration of RNA, DNA or protein.

The Techne Sample Concentrator is supplied with a three-year warranty and can be used with either a nitrogen generator or gas cylinder.

The lightweight and compact unit can easily be placed in a fume cupboard when toxic solvents are being evaporated.

PTFE-coated needles are available for use with corrosive chemicals.

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Potent Novel Tool For Combating Autoimmune Diseases And Leukemia

Last Updated on Thursday, 28 January 2010 06:10 Written by Editor Thursday, 28 January 2010 06:10

A study carried out by the scientists at the Scripps Research Institute illustrated a novel, highly practical strategy for identifying molecules that avert a particular form of immune cells from launching assaults on their host. These findings have added a potent new-fangled tool to the ongoing investigation for probable treatments for autoimmune diseases like MS or multiple sclerosis

, as well as for the treatment of types of leukemia like myeloid leukemia.

The study conducted by Thomas Kodadek, a professor in the Chemistry and Cancer Biology Departments, Scripps Florida, and associates was printed in the â€˜Chemistry & Biologyâ€™ Journal.

In the novel study, Kodadek and his associates utilised samples taken from an animal model of MS for screening for T cells â€“ a kind of white blood cell that dons fundamental role in the immune system â€“ with an increasing presence in the ailment. The screen additionally recognized molecules that interfered with such T cellsâ€™ auto-reactive nature or their assault on the body itself instead of a foreign intruder like a virus or bacteria.

Autoreactive t cells Kodadek stated that their method concurrently unearths and separates auto-reactive T cells along with inhibitors to them. A dual achievement at the core of which is a relative screening procedure of healthy T cells vs. Disease-causative T cells. Even as the process is technically complex and intricate, the thought behind it is not. The scientists intended to make the process of recognizing compounds simpler that could hinder auto-reactive T cells with outstanding specificity and the scientists were able to accomplish their objective.

The scientists employed a model of MS â€“ an autoimmune inflammatory condition that affects the brain and the spinal cord for the study. MS is a condition wherein the immune system assaults the myelin sheath coating and defensive nerve cells that lead to a host of symptoms dependent on what component of the nervous system has been affected. Prevalent signs of the condition involve weariness, numbing sensation; difficulties experienced in walking balancing and co-ordination; dysfunctional bladder and bowel; ocular problems; giddiness and vertigo; sexual dysfunction problems; pain, mental problems; emotional variations and spastic behaviours.

Simplification of the Process

Kodadek and his associates set up the novel method for shedding light on these autoimmune diseases and other kinds of disorders and produced a vast assortment of peptoids â€“molecules linked to, though more constant as compared to the peptides which made up the proteins. By organizing thousands of the peptides microscopically, the prototype of binding antibodies (a form of autoimmune molecule) and peptoids could be pictured. By observing samples drawn from animal models of an identified disease such as MS, peptoids which exhibited binding to antibodies closely linked with that disease could be easily identified.

Even better, peptoids which showed binding to the autoreactive T cells could be spotted with no awareness of the particular antigen (molecules that elicit the immune assault), offering an impartial approach with which to explore potentially beneficial compounds.

Kodadek stated that they had made a breakthrough where they set up a system that identifies T cell receptors which are copious in an ailing animal and in sapped levels in a healthy animal.

Potential for Curative Breakthrough

The novel process created a novel potential for curative finding. Molecules that targeted auto-reactive T cells in a direct way, while overlooking those T cells that identify foreign antigens, could provide the basis for a new drug development program intended at elimination of autoreactive cells with no affect on the normal functioning of the immune system.

Kodadek stated that the novel study is not the ultimate solution as it employed a model of MS elicited by a sole antigen whereas in human beings there could be 2 to even more antigens that trigger an autoimmune disease like MS that needs further investigation. The method could be applicable with ease to blood cancers, although as the disease-causative T cells have been completely characterized and there being quite a few of them.

Source: simplehealthguide.com

Posted under Medicinal Chemistry, Press Releases, R & D | Comments Off

Karwar scientistâ€™s theory to â€˜weedâ€™ out CO2

Last Updated on Thursday, 28 January 2010 06:05 Written by Editor Thursday, 28 January 2010 06:05

KARWAR: While representatives of 192 countries are engaged in climate change debates at Copenhagen, Dr Ullas Naik, a marine scientist at the department of marine biology, at Karnatak Universityâ€™s PG Centre, here has suggested the unassuming sea weed as a possible cure to the planetâ€™s ills.Calling for the scientific culture of algae, commonly known as sea weed and its conservation and protection, Naik points out that these algae provide much of the earthâ€™s oxygen. They absorb carbon dioxide from the environment and carry out photosynthesis to enhance the productivity.Naik, who presented a paper on his findings at a seminar at the university recently, says the discovery has shown that these marine weeds have a remarkable ability to detoxify serious organic pollutants such as TNT or polycyclic aromatic hydrocarbons.According to him, these algae have an intrinsic ability to detoxify TNT 5-10 times faster than any known terrestrial plant.Since some of the marine organisms, particularly marine invertebrates like clamps, shrimp, oyster or crab, the staple food for many, tend to accumulate toxins, growth of sea weeds will have important implications for sea food safety, he asserts.Marine algae contain protein (5- 10%), fat (0.5-1.5%), ash (10-18%), fibre (3-6%) and carbohydrates (40-60%). He says they are rich in minerals and vitamins and can be used as food.The bioactive compound found in seaweeds have variety of applications in pharmaceutical field. Naik says attempts should be made for screening pharmaceutically active compounds from seaweeds. In fact, seaweeds will be the medicinal food of this century, Naik opines.Cautioning that these â€œwonderful marine speciesâ€™â€™ should be explored scientifically, he says they can be used as manure and fodder.

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Hi-tech microscopes make androgen therapy ‘personal’

Last Updated on Thursday, 28 January 2010 06:03 Written by Editor Thursday, 28 January 2010 06:03

HOUSTON — (December 9, 2009) — On rare occasions, an infant is born with outward appearance of a female but the XY chromosomes of a male. If the child has a normal Y chromosome — the chromosome responsible for testicular development — the condition is known as androgen insensitivity syndrome.

Experts estimate such births occur in about one in 20,000 infants. Other children are born with a partial form of the condition that can affect their genitalia and/or fertility, but how many is not known.

The cause is a wide range of androgen receptor (AR) mutations that fail to perceive the presence of the male hormones testosterone and dihydrotestosterone to differing degrees. How to overcome the problem remained a mystery until Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center experts used a high throughput, automated microscopy technique called high content analysis to solve the puzzle. A report of their findings appears in the current issue of PLoS One, an open access journal.

Reverse effect of mutation

They not only identified the functional abnormality of the AR, but also used high content analysis to “personalize” a treatment that reverses the effects of that mutation.

“With this microscopy technique, we have been able to quantify how the receptor moves and functions inside cells taken from children with normal receptors and in those with the mutation,” said Dr. Marco Marcelli, professor of medicine-endocrinology at BCM and a physician at the Michael E. DeBakey Veterans Affairs Medical Center. He and Dr. Michael Mancini, associate professor of molecular and cellular biology at BCM, and director of its Integrated Microscopy Core, are senior authors of the report.

Androgen insensitivity syndrome

They used banked cells taken from patients â€“ both those with the mutation and those without â€“ to study the action of the receptor in cell cultures grown in the laboratory. Dr. Michael J. McPhaul, a collaborator on the study and a professor of internal medicineâ€”endocrinology at The University of Texas Southwestern School of Medicine Dallas, provided the samples from patients with androgen insensitivity syndrome.

“We did this on a cell-by-cell basis, using high content analysis,” said Mancini. “It is a proof-of-principle study carried out as though we had a patient and a library of hormones. We tried to find the perfect hormone for the mutation through high-speed collection of dozens of measurements from thousands of cells.”

“In two of the three specimens we tested, we found we were able to reverse the activity of the mutated receptor to almost normal,” said Marcelli.

In one patient, large doses of the male hormone dihydrotestosterone were sufficient. In another, they used a synthetic androgen that also activated the receptor.

These approaches overcame the central problem â€“ the mutation changes the shape of the receptor and prevents it from maintaining normal contact with the hormone. It is as though a key is bent and can no longer turn the tumblers in a lock. In these cases, the hormone is designed to go into a pocket created by the receptor. When the pocket is changed by the mutation, the hormone is unable to establish good contact.

“Large amounts of testosterone may create more stable contact,” said Marcelli. “The synthetic androgen may have a conformation that establishes better contact.”

Superandrogen

In the future, scientists may be able to screen large banks of such compounds to find a “superandrogen” that may be even more efficient.

“We might be able to use this technique to create a personalized medicine test,” said Mancini.

Similar techniques might be used to screen drugs for treatment of different cancers, particularly those in which the androgen receptor is responsible for cancer progression. This study proves that the concept is valid providing quantitative information collected quickly on numerous measurements normally requiring separate biochemical tests and huge numbers of cells.

Marcelli said they have yet to use this kind of technique in patients, and such studies will require careful preparation, and go through a variety of approvals before it can be used in clinics. He also said it would be used only in individuals with the partial form of the syndrome. Finding well-matched hormones to defective androgen receptors through screening of thousands of compounds from available libraries could be one of the future developments of this technique.

The paper’s first author, Dr. Adam T. Szafran, an M.D./Ph.D. student who worked in Mancini’s laboratory, championed these studies, said Mancini. Szafran is now finishing the clinical part of his studies at BCM.

Others who took part in this study include Drs. Sean Hartig and Ivan P. Uray, Maria Szwarc, Jennifer Bell, Huiying Sun, Yuqing Shen and Sanjay N. Mediwala, all of BCM. Sun, Shen and Mediwala are also of the MEDVAMC.

Funding for this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the John S. Dunn Foundation and the Veterans Administration.

Source: bcm.edu

Posted under Compound Screening, Discoveries, Innovations and Patents, Press Releases | Comments Off

2009: The Year That Was For Pfizer

Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Thursday, 28 January 2010 04:46

(RTTNews) – True to expectations, Jeffrey Kindler, the CEO of Pfizer Inc. (PFE | Quote | %20%20%20%20%20%20 PFE%20|%20%20%20%20%20%20%20Quote%20|%20%20%20%20%20%20%20Chart%20|%20%20%20%20%20%20%20News%20|%20%20%20%20%20%20%20PowerRating“);”>Chart | News | PowerRating), scripted a new playbook for the drug giant in 2009, accelerating the process of transformation by clinching the largest pharmaceutical deal in nearly a decade.

The acquisition of Wyeth for $68 billion earlier this year represents a major move by Pfizer to plug the impending holes in its balance sheet when patents covering some of its key drugs expire in the next few years. Between 2010 and 2012, drugs that make up 42% of Pfizer’s pharmaceutical revenue, are slated to lose patent protection.

Let’s take a look at some of the Pfizer news that made headlines this year.

The Mega Deal

Though Pfizer is not new to mega deals, Kindler was dubious of such mega mergers till last year. He preferred only bolt-on or product acquisitions to major acquisitions. However, the craving for new sources of revenue and the inability of the company’s near-term pipeline to make up the slack when its blockbusters lose patent exclusivity made Kindler adopt the mega-merger strategy this year and acquire Wyeth.

Wyeth has a promising pipeline as well as a number of blockbusters in its arsenal, including rheumatoid arthritis drug Enbrel, jointly marketed with Amgen (AMGN | Quote | Chart | News | PowerRating), pneumonia vaccine Prevnar, antidepressant Effexor, nutritional products, intravenous antibiotic Zosyn and the hormone replacement therapy Premarin family of drugs. Enbrel topped $3 billion in total sales, Effexor raked in worldwide revenue of $3.93 billion, while Prevnar notched up sales of $2.72 billion in 2008.

As mentioned above, drugs that make up 42% of Pfizer’s pharmaceutical revenue, are slated to lose patent protection between 2010 and 2012. The drugs going off-patent include Aricept, Lipitor, Viagra, Detrol, Geodon and Xalatan. Lipitor alone accounted for 28% of Pfizer’s pharmaceutical sales last year.

Pfizer’s revenue in 2008 was $48.3 billion, while Wyeth’s revenue for the year totaled $22.8 billion. With highly complementary businesses, the combined company has a diverse product portfolio that includes 17 products with more than $1 billion each in annual revenue. It is expected that no drug will account for more than 10% of the combined company’s revenue in 2012.

The combination also brings together a robust pipeline of biopharmaceutical research and development projects, including programs in diabetes, inflammation/immunology, oncology and pain, as well as significant opportunities in Wyeth’s Alzheimer’s disease pipeline.

Pfizer completed the acquisition of Wyeth in October, nine months after the companies inked a definitive merger agreement. The acquisition is expected to be accretive to Pfizer’s adjusted earnings per share in the second full year after closing and yield cost savings of about $4 billion to be fully realized by the third year after closing.

No doubt, the acquisition of Wyeth will provide a more diversified portfolio and alleviate Pfizer’s sales decline, but this will not be the panacea for the threat caused by the raft of patent expirations, according to research firm Datamonitor. Wyeth also faces looming patent expiration on its key drug Effexor XR. The depression drug, which notched up $3.93 billion in sales last year, is slated to lose patent exclusivity in 2010.

However, as the company gets rid of operational overlap, the deep cost cuts will see the combined company delivering profit growth.

For 2009, Pfizer now expects reported earnings to range between $1.45 and $1.50 per share and adjusted earnings to range between $2.00 and $2.05 per share. Previously, the company was anticipating reported earnings to range between $1.30 and $1.45 per share and adjusted earnings to range between $1.90 and $2.00 per share. The company now expects reported revenues in the range of $49 billion-$50 billion, up from its prior forecast of $45 billion-$46 billion. The revised guidance reflects the completion of the Wyeth transaction.

Cost-cutting measures in full gear

Pfizer has been in restructuring mode since 2005 and has retained its focus on cutting costs, including outsourcing and offshoring to ease the pressure on its topline.

Since 2005, Pfizer has significantly reduced its workforce. According to the company’s quarterly filing with the SEC, from June 2005 through September 27, 2009, it terminated 26,300 of its employees and has expensed employee termination costs of $5.35 billion.

In tandem with its merger with Wyeth, Pfizer is in the process of laying off 15% of the combined company’s workforce. That includes the 10% workforce reduction announced earlier this year. In the first nine months of 2009, the company reduced its workforce by approximately 6,500 employees. The company’s aggressive belt-tightening measures are expected to generate significant cost reductions for the combined company.

Pfizer anticipates achieving total annual cost savings of about $6 billion by the end of 2012. The targeted savings include $2 billion in net cost reductions from Pfizer cost-reduction initiatives, of which about $950 million has been achieved through September 27, 2009, and an additional $4 billion in expected synergies related to the integration of Wyeth.

The Neurontin Controversy

There are about 1,200 lawsuits over Pfizer’s off-label marketing of Neurontin. While the drug was originally approved by the FDA as an add-on treatment for partial epileptic seizures in 1993 and for the management of post-herpetic neuralgia in 2002, Pfizer has been marketing it to treat multiple conditions including mood swings and arthritis. In 2004, Pfizer paid $430 million in fine to settle civil and criminal charges of promoting Neurontin for unapproved uses.

The first lawsuit against Pfizer, in regard to Neurontin came to trial in July of this year. The suit was filed by the family of Susan Bulger, a 39-year-old woman who committed suicide in 2004. Bulger had been prescribed Neurontin for arthritis, an off-label use, and was taking the drug for two years. However, after just one day of testimony, Bulger’s family dropped the case against Pfizer after an anonymous donor offered to set up a trust for the deceased woman’s 10-year old daughter.

A review of Neurontin trial results published by Kay Dickersin last month in the New England Journal of Medicine, accuses Pfizer of manipulating the trial data for various unapproved indications. The author Kay Dickersin was an expert witness in the trial. Pfizer, which has disputed the findings of the article, said the review published in the journal was “derived from a report created for litigation and coauthored by plaintiffs’ expert witness, who was hired to produce opinions to support plaintiffs’ arguments.”

Though the first case involving Neurontin has been dismissed, this legal tangle is far from over. However, Pfizer firmly believes that there is no scientific evidence to prove that Neurontin causes suicidal behavior.

The basic U.S. patents relating to Neurontin expired in 1994 and 2000. However, in April 2000, a U.S. patent was granted relating to stable pharmaceutical compositions of Neurontin containing low levels of lactam impurity. This patent expires in 2017.

Neurontin, which once fetched $2 billion in sales for Pfizer, began to face generic competition in the U.S. in the latter half of 2004. Subsequently, the pharma giant launched its own generic version of Neurontin in the U.S. through its Greenstone Ltd. generic pharmaceutical subsidiary. In 2008, the global sales of Neurontin totaled $387 million, a decline of 10% from 2007. For the nine months ended September 2009, Neurontin sales declined 18% to $242 million from the comparable period a year before.

Major legal settlements

Pfizer, which is no stranger to legal tussles, got itself cleared of some of the legal issues this year by settling with the plaintiffs. After all, legal beagle Kindler knows that closure of significant legal matters will only help his company to enhance its focus on discovering, developing and delivering innovative medicines.

On July 30, Pfizer settled the long drawn-out lawsuit with Kano State government in Nigeria related to the company’s 1996 study of antibiotic drug Trovan.

The suit filed by authorities in Kano accused Pfizer of administering the untested and unapproved antibiotic called Trovan to children during a meningitis epidemic in 1996, resulting in the deaths of an unspecified number of children and leaving others deaf, paralyzed, blind or brain-damaged.

According to the lawsuit, Pfizer did not obtain consent from the children’s families before enrolling the children in the ill-fated trial. The suit also accused Pfizer of conducting the study of Trovan despite knowing the life-threatening side effects of the drug and being well aware that it was unfit for human use. However, Pfizer has denied any wrongdoing or liability in connection with the 1996 study.

Under the terms of the settlement, Pfizer agreed to pay $30 million over a period of two years to support health initiatives designated by Kano State and to reimburse Kano State for $10 million in legal costs associated with the litigation.

Pfizer has also agreed to establish a Healthcare/Meningitis Fund from which study participants can receive financial support. The maximum amount that could be disbursed by the Fund is $35 million, but the final amount will depend on the total number of valid claims submitted.

In turn, Kano State agreed to dismiss both the civil and criminal Trovan-related cases it filed against Pfizer and various individuals.

Yet another lawsuit that Pfizer resolved this year is a multi-billion dollar settlement and the largest healthcare fraud settlement in the history of the Department of Justice. Pleading guilty to a felony crime in off-label promotional practices for painkiller Bextra, which was withdrawn from the market in 2005 over safety concerns, and fraudulent marketing of anti-psychotic drug Geodon, antibiotic Zyvox and anti-epileptic drug Lyrica, Pfizer on September 2 announced it agreed to pay $2.3 billion in fines to settle federal criminal and civil charges against it. The fine was already factored into the fourth-quarter earnings of 2008 and no additional charges are expected to be carried over.

In October, the drug giant entered into an agreement with drugmaker Mylan Inc. (MYL | Quote | Chart | News | PowerRating) related to a generic version of Vfend (voriconazole), an antifungal agent. In the same month last year, Matrix Laboratories Ltd., the India-based subsidiary of Mylan, challenged Pfizer’s patents for its Vfend tablets, 50 mg and 200 mg, with the filing of its Abbreviated New Drug Application.

However, Pfizer did not file a lawsuit against Matrix within the statutory 45-day time period. Now that Pfizer has entered into an agreement with Mylan, the generic drugmaker will have the right to market voriconazole tablets in the U.S. in the first quarter of 2011. The details of the agreement with Mylan were not disclosed. Vfend logged in sales of $743 million in 2008 and $555 million for the nine months ended September 2009.

Not out of legal woods…

Though Pfizer has settled some of its long-standing legal issues, it is not completely out of the legal woods. In addition to its own legal hassles, Pfizer also has to resolve Wyeth’s legal woes inherited through the acquisition.

Wyeth’s hormone replacement therapy drugs, Premarin and Prempro touted as “magic bullets” are indicated for the relief of hot flashes and night sweats, associated with menopause. After the U.S. government’s Women’s Health Initiative study found that healthy postmenopausal women enrolled in the study who were treated with the hormone replacement therapy drugs, Premarin and Prempro had increased risk of invasive breast cancer, stroke and blood clots, Wyeth came under fire. The study, which was to continue until 2005, came to an abrupt halt in early June 2002. However, the drugs continue to be in the market.

Wyeth faces lawsuits from more than 10,000 women who claim that the company’s hormone-replacement therapy drugs Premarin and Prempro caused breast cancer.

In the trial related to hormone-replacement therapy drugs, two verdicts were announced this year, and Wyeth, now a division of Pfizer, has been ordered to pay $103 million in punitive damages in the two cases.

Wyeth has not set aside any legal reserve for dealing with the hormone replacement therapy litigation and settlements.

Regulatory Approvals

Pfizer spends more than $7 billion annually on research and development. Last year, the company abandoned its research projects related to heart disease, obesity and bone health to focus on lucrative fields like cancer and Alzheimer’s.

According to the company’s latest pipeline update, the areas of focus include allergy & respiratory; cardiovascular, metabolic and endocrine diseases; gastrointestinal; genitourinary; infectious diseases; inflammation; neuroscience; oncology; ophthalmology and pain.

The following are few of Pfizer’s drugs that won regulatory approval this year.

A Double Treat

It was a double treat from the FDA for Pfizer on November 20, as the drug giant won approval for two of its drugs the same day.

Pfizer’s antipsychotic Geodon won expanded FDA approval for maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate in adults.

The drug is already FDA-approved as a monotherapy in the treatment of acute manic and mixed episodes associated with bipolar disorder, with or without psychotic features, and for the treatment of schizophrenia.

Since the FDA approval of Geodon in February 2001, nearly 2 million adult patients have been treated with this drug. Unlike other antipsychotics, Geodon is not associated with weight gain. The drug raked in global sales of $1 billion last year and $713 million for the nine months ended September 30, 2009.

Pfizer also received FDA approval for the intravenous formulation of Revatio for the continued treatment of patients with pulmonary arterial hypertension who are currently prescribed Revatio Tablets but who are temporarily unable to take oral medication.

Pulmonary arterial hypertension is a rare, progressive disease that affects an estimated 100,000 men and women worldwide. This incurable disease is characterized by continuous high blood pressure in the pulmonary arteries, often leading to heart failure and premature death.

Revatio Tablets were approved by the FDA in June 2005 and by the European Medicines Agency, or EMEA, in November 2005. Revatio contains the same active ingredient as Viagra, which is used to treat erectile dysfunction (impotence). Pfizer doesn’t break out Revatio sales when reporting its quarterly results, so there are no specific numbers on the drug’s sales.

The first canine cancer drug

All these years, veterinarians had to rely on human oncology drugs without knowledge of how safe or effective they would be for dogs. Cancer treatments used in animals are used in an “extra-label” manner as allowed by the Animal Medicinal Drug Use Clarification Act of 1994. However, dog owners, in consultation with their veterinarian, now have an option for treatment of their dog’s cancer.

On June 3, the FDA approved Palladia (toceranib phosphate), the first drug developed specifically for the treatment of cancer in dogs. According to the Morris Animal Foundation, which is dedicated to funding animal health research, 1 in 4 dogs die of cancer. About 1.2 million new canine cancer cases are reported in the U.S. every year. The product is expected to be available for purchase in early 2010.

U.K.’s NICE becomes nice to Sutent

Reversing its earlier stance, the United Kingdom’s NICE (National Institute for Health and Clinical Excellence), which evaluates the cost-effectiveness of medications, recommended reimbursement for kidney cancer drug Sutent as a second-line treatment for patients with advanced gastrointestinal stromal tumor.

The decision of NICE gives hope to patients with gastrointestinal stromal tumors who develop resistance to Imatinib (Novartis’ (NVS) Gleevec), according to Pfizer. It is estimated that about 7,000 people in the U.K. are diagnosed with kidney cancer every year and that 3,600 patients are eligible to receive Sutent since they have an advanced form of the disease.

Last year, NICE rejected four kidney cancer drugs including Sutent for the treatment of advanced and/or metastatic forms of renal cell carcinoma within the National Health Service due to financial considerations.

In international markets, the sales growth of Sutent continues to outpace its growth in the U.S. In 2008, Sutent’s annual sales in the U.S. were up a mere 7% to $254 million, while international sales of the drug rose 72% to $593 million. In the third-quarter ended September 30, 2009 Sutent generated U.S. sales of $192 million, an increase of 2% over the comparable quarter last year, while international sales of the drug totaled $479 million, an increase of 9% over the year-ago quarter.

Old Drug, New use

Pfizer remains committed to expand its HIV drug Selzentry’s current indications. The company is seeking approval of Selzentry in treatment of adult patients with CCR5-tropic HIV-1 virus as part of combination therapy.

In October, an FDA panel recommended the expanded use of Selzentry in treatment-naÃƒÆ’Ã‚Â¯ve patients. The FDA is scheduled to make a final decision in the coming months.

Selzentry was granted accelerated approval in August 2007 and full approval in November 2008 by the FDA for use in patients with resistant HIV strains or who do not respond favorably to multiple antiretrovirals.

According to AIDS Healthcare Foundation, Selzentry’s price has increased 10% since its approval in 2007 two years ago to $13,767 per-patient per year. If approved for the expanded use, Selzentry would become the most-expensive first-line AIDS drug.

A shot at vaccines

For Pfizer, vaccine innovation is a key strategic priority and an expression of its vision to broaden and diversify its global product portfolio.

On November 18, the FDA’s Vaccines and Related Biological Products Advisory Committee voted 10 to 1 recommending Prevnar 13 for the prevention of invasive pneumococcal disease in infants and young children. The FDA is scheduled to make a final decision on Prevnar 13 on December 30, 2009.

In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use issued a positive opinion for Prevenar 13. A final decision is expected by European regulatory authorities in December. Additionally, the vaccine is being studied in global phase-III clinical trials for the prevention of pneumococcal disease in adults, with regulatory submissions expected in 2010.

Prevnar 13 targets thirteen strains of bacteria known as streptococcus pneumoniae, while Prevnar, which has been in the market since 2000, targets only seven strains of bacteria. Prevnar is Wyeth’s second top-selling drug and had global sales of about $2.7 billion last year.

Clinical Trial Missteps and Regulatory Knockdowns

This year, the pharma behemoth endured failure in a number of late-stage trials, raising concerns about its R&D department.

Jan.30 – Pfizer halted a phase III study of its investigational agent axitinib for the treatment of advanced pancreatic cancer following no evidence of improvement in the primary endpoint of survival in patients treated with axitinib and gemcitabine compared to gemcitabine alone. However, the company is investigating axitinib in renal cell carcinoma where it is currently in a late-stage testing for second-line treatment.

Feb.24 – Two late-stage development programs for investigational compounds esreboxetine for fibromyalgia and PD 332,334 for generalized anxiety disorder were terminated as neither was found to be better than the current standard of care. Pfizer already has an FDA-approved medicine for the treatment of fibromyalgia sold under the brand name Lyrica. The company plans to pursue expanded indication for Lyrica in the treatment of generalized anxiety disorder, a condition that overlaps with fibromyalgia.

April 2 – Pfizer’s phase III program of Sutent suffered its first blow of the year when a trial evaluating the drug for breast cancer indication had to be halted. The trial dubbed SUN 1107 evaluated single-agent Sutent versus single-agent capecitabine for the treatment of a broad range of patients with advanced breast cancer after failure of standard treatment. An independent Data Monitoring Committee found that Sutent would be unable to demonstrate a statistically significant improvement in the primary endpoint of progression-free survival.

June 1 – The phase III program of Sutent suffered yet another blow when the company had to halt a trial dubbed SUN 1094 that evaluated Sutent plus paclitaxel versus bevacizumab plus paclitaxel for the first line treatment of patients with advanced breast cancer. The independent Data Monitoring Committee found that treatment with Sutent in combination with paclitaxel would be unable to meet the primary endpoint of superior progression-free survival (PFS | Quote | Chart | News | PowerRating) compared to the combination of bevacizumab and paclitaxel. No new safety issues were identified.

June 30 – Another late-stage trial of Sutent to bite the dust was that of the metastatic colorectal cancer study. The trial dubbed SUN 1122 evaluated Sutent plus chemotherapy drug combination FOLFIRI versus FOLFIRI alone for the first-line treatment of metastatic colorectal cancer. The independent Data Monitoring Committee found that the addition of Sutent to the chemotherapy regimen FOLFIRI would be unable to demonstrate a statistically significant improvement in the primary endpoint of progression-free survival compared to FOLFIRI alone.

Oct.9 – Following recommendations of an independent safety monitoring committee, Pfizer temporarily stopped enrolling new patients in a late-stage trial dubbed Advigo 1016 that was evaluating its experimental lung-cancer compound Figitumumab. The primary objective of the trial is to determine whether the addition of Figitumumab in combination with paclitaxel and carboplatin prolonged survival in patients with non-small cell lung cancer.

An independent safety monitoring committee overseeing the study found more serious adverse events, “including fatalities, in patients who were randomized to receive figitumumab,” than in patients who didn’t receive the investigational drug. Figitumumab, with estimated sales potential of $400 million to $1.2 billion by 2015, was one of the drugs that Pfizer had been counting on to replace sales of Lipitor when it loses basic patent protection in the U.S. in March 2010. The second patent covering the calcium salt of atorvastatin, the active ingredient in Lipitor, expires in June 2011.

However, another late-stage lung cancer study testing Figitumumab in combination with Roche Holding Ltd.’s (RHHBY.PK) and OSI Pharmaceuticals Inc.’s (OSIP | Quote | Chart | News | PowerRating) Tarceva is continuing to enroll new patients, according to Pfizer.

Third time’s no charm for Fablyn

On January 16, the FDA issued a complete response letter for Pfizer’s investigational osteoporosis drug Fablyn (lasofoxifene) and sought additional information.

Last September, an FDA panel voted 9 to 3, endorsing Fabyln. Though study results of Fabyln have demonstrated its efficacy in treating osteoporosis in postmenopausal women, according to the FDA Administration advisory board briefing document, Fabyln increased the chances of cancer or stroke-related deaths. Other side effects include blood clots.

Fablyn, a selective estrogen receptor modulator, or SERM, was developed by Pfizer with the help of screening technology licensed from Ligand Pharmaceuticals Inc. (LGND | Quote | Chart | News | PowerRating).

It was Fablyn’s third go-around with the FDA. The FDA rejected Fablyn as a medicine for the prevention of post-menopausal osteoporosis in September 2005 and for the treatment of vaginal atrophy in January 2006 on concerns that the drug may lead to cancer in the lining of the uterus.

However, the drug received approval from the European Commission in March of this year for the treatment of osteoporosis in post-menopausal women at increased risk of fracture.

Late-stage pipeline

Pfizer has more than twenty phase III programs and Wyeth has more than five late-stage trials that are currently underway.

Wyeth is also conducting a late-stage trial evaluating Pristiq for the non-hormonal treatment of vasomotor symptoms associated with menopause. The FDA, which issued an approvable letter for Pristiq in July 2007, has sought additional data regarding the potential for serious adverse cardiovascular and hepatic effects associated with the use of Pristiq for the treatment of menopausal symptoms. The requested clinical trial that is underway is expected to be completed in the first half of 2010.

In the first half of 2009, Mexico and Thailand granted approvals for Pristiq for the treatment of menopausal symptoms.

Viviant is yet another Wyeth drug waiting to pass muster with the FDA. The investigational postmenopausal osteoporosis pill has been twice at the FDA altar – in December 2007 and May 2008 – only to be turned down. In its approvable letters, the regulatory agency had requested further analyses and discussion concerning the incidence of stroke and venous thrombotic events and requested additional source documents related to Viviant.

In a recent SEC filing, Wyeth said the FDA will be convening an advisory committee to review its pending New Drug Application for Viviant. Wyeth expects the FDA-requested advisory committee meeting will be scheduled following submission of its complete response to the approvable letters, which are planned for filing later this year.

The EU trade name for Viviant is Conbriza and the drug was approved for the treatment of postmenopausal osteoporosis in women at increased risk of fracture in April of this year. The drug is expected to hit the pharmacy shelves in the EU next year.

In July, Wyeth announced new positive results from a late-stage trial of Aprela, a drug under development for menopausal symptoms and osteoporosis. An initial NDA for Aprela is expected to be filed no earlier than the first half of 2010.

In December, Pfizer made an entry into the market for orphan drugs by acquiring worldwide rights to Uplyso, an experimental drug for Gaucher’s disease, a rare genetic disorder, from Israeli biotech firm Protalix BioTherapeutics Inc. (PLX | Quote | Chart | News | PowerRating). The current standard of care for Gaucher patients is enzyme replacement therapy and Genzyme Inc. (GNZ | Quote | Chart | News | PowerRating)’s Cerezyme is currently the only approved enzyme replacement therapy for Gaucher disease. Last year, Cerezyme fetched $1.2 billion in sales for Genzyme. Protalix is close to complete a rolling New Drug Application submission for Uplyso with the FDA. The product is expected to reach the market next year.

Eyeing generic drug pie

It is no secret that Pfizer has been vying for a greater share of the generic drug market. The drug giant estimates that the global generic business is set to grow to $500 billion by 2012 from $270 billion in 2006.

Early last year, the company formed an Established Products Business Unit to execute growth strategies tailored to the unique needs of branded emerging markets (such as China, India, Brazil and Russia), branded traditional markets (such as Japan, Western Europe and South Korea), and intellectual-property-driven markets (such as the United States and Canada).

Pfizer’s global annual sales of established products are approximately $10 billion. (Established products are medicines that have lost or will soon lose patent protection).

In May, Pfizer entered into agreements with India-based Claris Lifesciences Ltd. to commercialize 15 sterile injectable medicines after the products are no longer patent protected and have lost market exclusivity in North America, Europe, Australia and New Zealand.

The same month, Pfizer expanded its agreements with Aurobindo Pharma Ltd. in India by acquiring rights to 55 solid oral dose products and 5 sterile injectable products for patients in more than 70 emerging market countries.

Closing Thoughts

Shares of Pfizer, which touched a 12-1/2 year intra-day low of $11.62 in March, have since recovered nearly 55% and currently trade around $18. As the now streamlined, more flexible and strategically grounded Pfizer gets ready to face another new year, will there be a change in investors’ ho-hum attitude towards the stock?

Source: tradingmarkets.com

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Model for powerful flu fighters from existing drugs

Last Updated on Thursday, 28 January 2010 04:34 Written by Editor Thursday, 28 January 2010 04:34

Computer compatibility tests might help flu-fighting drugs find their groove.

A pandemic of the H1N1 swine flu virus has health officials worried that the virus could develop resistance to drugs such as Tamiflu used to treat infected people. A new computerized screening method could help find new or already existing drugs that find a flu virusâ€™ weak spot, researchers from the University of California, San Diego reported December 6 at the annual meeting of the American Society for Cell Biology.

Researchers Daniel Dadon, Jacob Durrant and J. Andrew McCammon, all of UCSD, made a computer movie of slight structural shifts occurring in the neuraminidase 1 enzyme (the N1 in H1N1 and H5N1), a protein found in the avian and swine influenza viruses. Those changes reveal possible target areas that could allow drugs to circumvent a virusâ€™ usual means of becoming resistant.

All influenza viruses have a neuraminidase enzyme, but the protein comes in several subtypes. Previous work had shown that the N1 subtype contains a loop that makes it more flexible than other neuraminidase subtypes, says Rommie Amaro, a computational biologist at the University of California, Irvine. â€œIt is particularly nimble,â€ she says. The enzymeâ€™s flexibility could affect the way drugs bind to it.

Enlarge

Antiviral drugs can wedge into a cavity within an active site of the N1 neuraminidase enzyme (blue) and stop the enzyme’s action. Mutations in the enzyme (colored dots) can reduce the efficiency with which antiviral drugs such as Tamiflu bind, creating drug-resistant forms of the virus. Newly discovered drugs (green) lodge in the enzymeâ€™s active site in a different location, possibly being able to knock out viruses that have become resistant to other drugs.Daniel Dadon and Jacob Durrant, University of California, San Diego

Analyses of still frames from the simulation, which is called a relaxed complex scheme, revealed 27 different natural conformations that the N1 protein could take on under conditions it might encounter in a host cell. Some parts of the protein change shape readily and some stiffer portions are locked into place, the researchers discovered.

Drugs currently used against flu â€” including oseltamivir, better known as Tamiflu, peramivir and zanamivir â€” all insert themselves into neuraminidase at about the same location within that enzyme. When the drugs insert into that pocket, they block the enzymeâ€™s ability to release newly made viral particles from the cell, and this blockage prevents the spread of the disease.

That location is prone to structural changes such as those revealed by the simulation, and to genetic changes that affect the amino acid building blocks that compose the protein. Many of those amino acid changes also alter the shape of the pocket, keeping the drugs from binding and thus making the flu virus resistant to the drugs.

To find drugs that could block the protein’s active site in a different way â€” and knock out viruses resistant to the currently used drugs â€” the researchers mined a library of FDA-approved drugs. The team digitally sliced up the drugs and simulated how the drug fragments might bind to all of the enzymeâ€™s forms.

Among those fragments, the team found 15 novel compounds that could wedge into the proteinâ€™s pocket and block its action better than Tamiflu or other antiviral drugs would. A closer examination revealed that those 15 compounds share a common structure. What’s more, the compounds lodge into a part of the protein that doesn’t allow changes easily, meaning that those areas are less likely to mutate and develop drug resistance than the parts of the protein that come into contact with Tamiflu and other current flu treatments, Dadon says.

But because the computer-generated fragment molecules don’t exist in the real world, the researchers needed to see whether any existing, small molecules could work just as well. Searching four databases of drugs turned up six small molecules that had the same common structure as the digitally diced compounds. These real compounds are currently being tested by collaborators in Australia to determine whether they really do block the flu’s action.

Both of the approaches Dadonâ€™s team followed in the new drug design scheme â€” examining all forms of the protein and then screening a library of fragments from approved drugs â€” could be easily adapted for other molecules, Amaro says. The caveat is that researchers need to have prior knowledge of an enzymeâ€™s structure in order to develop effective drugs, she says.

Source; Sciencenews.org

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Therasis Obtains $12 Million From Tilocor in Series A Round

Last Updated on Thursday, 28 January 2010 04:30 Written by Editor Thursday, 28 January 2010 04:30

NEW YORK, NY -- 12/08/09 -- Therasis, Inc., a newly founded oncology drug discovery company, has secured $12 million in a Series A financing from Tilocor Life Science. The funds will allow the Company to launch and further develop its proprietary oncology drug discovery engine, the Therasis Filter(TM). This platform employs a systems biology approach and represents a significant advance over existing technologies, enabling the identification of new chemical entities, biomarkers and synergistic combinations through the construction and analysis of tumor-derived molecular interaction networks. The Company's initial efforts will focus on developing an internal pipeline of oncology drug candidates and forming drug discovery collaborations with pharmaceutical and biotechnology companies."The Therasis Filter(TM) represents a paradigm shift in drug discovery that overcomes many of the hurdles in developing optimal anti-cancer therapies, in particular the ability to identify and target the multiple chemical pathways altered in a specific tumor subtype," said Andrea Califano, Ph.D., co-founder of Therasis. "This funding allows Therasis to build internal capacity and offer potential partners the unprecedented advantages of our screening technology, which greatly facilitates the identification of both disease-relevant activity as well as effective drug combinations."

Therasis was founded based on technology developed at the Herbert Irving Comprehensive Cancer Center by three internationally-recognized thought leaders: Dr. Andrea Califano, Director of the Joint Centers for Systems Biology at Columbia University and Associate Director of the Herbert Irving Comprehensive Cancer Center; Riccardo Dalla-Favera, M.D., Director of the Herbert Irving Comprehensive Cancer Center; and Owen A. O'Connor, M.D., Ph.D., presently Deputy Director of Clinical Research and Cancer Treatment at the New York University Cancer Institute. Collectively, they bring unique expertise and decades of experience in cancer systems biology, cancer genetics and pathology, and small molecule discovery and drug development in hematological malignancies.

"The co-founders of Therasis have individually made impressive contributions to their respective fields. The industrial translation of their combined academic leadership has the potential to make a real difference for cancer drug discovery," said Stefan Catsicas, Chairman of Tilocor. "Many academic and biotech groups have either systems biology, screening or chemistry outstanding expertise. But very few have managed to assemble all the necessary skills to truly transform how new oncology treatments are identified and developed."

About the Therasis Filter(TM)

The Therasis Filter(TM) enables the identification of disease-specific alterations in the networks of molecular interactions that regulate cellular processes, allowing the rapid identification of new chemical entities and synergistic combinations that target these alterations. Beginning with high throughput screening of compound libraries, the Therasis Filter(TM) first collects a large number of molecular profiles of chemically-perturbed cells. These profiles are used to reconstruct accurate maps of molecular interactions, also known as "interactomes." The latter are experimentally validated and analyzed to identify disease-specific alterations in tumor-derived tissues, compounds targeting these alterations and biomarkers complementing clinical development. Interactomes are also effective in characterizing drug mechanisms of action, supporting both drug rescuing and drug repositioning efforts.

About Therasis

Therasis, Inc. is a new drug discovery company developing oncology therapeutics for use as single agents or in combination therapy. The Company's proprietary technology, the Therasis Filter(TM), represents a paradigm shift in the ability to discover therapeutic targets, their chemical inhibitors and associated biomarkers. This platform integrates world-class expertise in high throughput screening, systems biology, cancer genetics and clinical research. Therasis plans to leverage its discovery engine to identify new chemical entities for internal development and to forge collaborations with pharmaceutical and biotechnology companies on drug repositioning.

Therasis's technology platform was developed at Columbia University by internationally recognized thought leaders in cancer genetics, cancer systems biology and cancer therapeutic development. The Company is funded by Tilocor Life Science. Learn more at www.therasis.com.

About Tilocor

Tilocor has established a small group of innovation-driven companies, working synergistically to better understand unmet medical needs and the new technologies that can be used to address them. Co-founded by Professor Stefan Catsicas, former Vice-President of the Swiss Federal Institute of Technology (Lausanne), the Tilocor Group promotes an entrepreneurial approach adapted to the long-term needs of the life science sector. Currently, Tilocor companies focus on inflammation, infectious diseases and cancer with specific therapeutic agents that include intracellular peptides, human antibodies and small chemical entities. More information is available at www.tilocor.com

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InformexUSA 2010

Last Updated on Friday, 22 January 2010 05:19 Written by Editor Friday, 22 January 2010 05:19

InformexUSA has become the leading resource for buyers and sellers of high-value chemistry for a broad range of applications. Todayâ€™s pharmaceutical innovators, agrochemical product makers, electronic materials producers and other manufacturers that come to Informex find what they need for business success: mainly new ideas that make a difference, and qualified companies with production assets that can make those ideas a reality.

We know you are aware of the value of participation in this event which will again feature a host of solutions, including:

Specialized Pavilions focusing on the hottest industry sectors

Breakfast Briefings that complement these sectors and more

And, Technology and Exhibitor Showcases highlighting leading-edge solutions and practices that can make all the difference in your future production.

Bottom line: if itâ€™s new â€“ itâ€™s happening at Informex! So, if you havenâ€™t made your plans to attend, you still have time â€“ but we urge you to do so today so you can take advantage of reduced hotel rates, advance information that assists in your planning and an ability to start dialoging with exhibitors to ensure that you are making the most of your attendance at Informex!

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Forma Therapeutics raises $25.5M in Series B round

Last Updated on Saturday, 24 July 2010 04:09 Written by Editor Monday, 11 January 2010 06:15

Forma Therapeutics has closed on a Series B financing that raised a total of $25.5 million. The round was led by new investor Lilly Ventures. Lilly was joined by existing investors Novartis Option Fund and Bio*One Capital of Singapore. Lexington-based Cubist Pharmaceutical, Inc. also joined as a new equity investor through a conversion of a previously issued note.

Steve Hall, a venture partner at Lilly Ventures, will join Formaâ€™s board of directors. The Cambridge-based company has a drug discovery technology platform designed to help develop new drug targets for cancer and other diseases.

â€œWith this new funding, Forma will focus on advancing our internal target-based oncology programs and in parallel, we will continue to pursue non-dilutive collaborations to further build our integrated drug discovery platform,â€ said Steven Tregay, CEO of Forma, in a statement.

More about Forma Therapeutics
Forma, which was founded in May of 2007, first announced a $25 million dollar series A financing round in January of 2009, followed a week later by a $200 million deal with the Novartis Option Fund, which gave the company its first $4 million in funding to launch.

Also in January, Forma entered a three-year collaboration agreement with Cubist Pharmaceuticals Inc. in which Cubist developed antibacterial compounds discovered by Forma. The deal calls for Forma to receive $14 million in upfront payments, delivery and research funding and equity; If Cubist pursues commercialization of the compounds, the deal could garner Forma another $54 million in milestones and royalties.

In July, Forma formed partnerships with The Leukemia & Lymphoma Society to move the health agencyâ€™s research products toward development quickly, and with Novartis AG to use Formaâ€™s cell-based screening platform to discover inhibitors for undisclosed protein-protein interaction targets to help develop cancer drugs.

Source: masshightech.com

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Anti-cancer compound wins scientist Biota Award

Last Updated on Monday, 11 January 2010 06:14 Written by Editor Monday, 11 January 2010 06:14

Walter and Eliza Hall Institute scientist Dr Guillaume Lessene has won this year’s Biota Award for Medicinal Chemistry, awarded by the Royal Australian Chemical Institute.

Dr Lessene, who runs a laboratory in the institute’s Structural Biology Division, won the award for his role in the discovery of several compounds that interact with a protein that has been implicated in the poor response of many cancers to anti-cancer treatments.

The protein is a member of the Bcl-2 family of proteins. This protein family has a role in tumour development, anti-cancer-drug resistance and cancer spread. Dr Lessene’s drug target, in particular, is thought to be involved in the drug resistance of many tumours.

The Biota Award is presented annually to the chemist judged to be responsible for the best drug design and development paper published, patent taken out, or commercial-in-confidence report concerning small molecules as potential therapeutic agents.

Together with eight co-inventors Dr Lessene has made a patent application that describes how his compounds could be used to restore the cell death process that is important in combating the growth of cancers.

Since 2001 Dr Lessene has focused his research on developing small molecules that inhibit the Bcl-2 family of proteins.

“It is expected that drugs targeting Bcl-2-like proteins will have a major impact in cancer treatment,” he said.

Usually, when a cell’s DNA is damaged the cell tries to repair itself and, if it can’t, undergoes a process of programmed cell death.

Cancer develops when, despite cells having DNA damage, they don’t die but continue to divide, leading to tumour formation. This happens when the signal that tells the cell to die is inhibited by Bcl-2 proteins, which allows the cell to keep dividing.

Through high throughput screening, medicinal chemistry, and structure-guided drug design, Dr Lessene and the institute’s drug discovery team have been identifying and refining compounds that inhibit the Bcl-2 proteins.

“From a drug discovery point of view the Bcl-2 proteins are challenging targets because of the size and shape of their binding sites,” Dr Lessene said. “Our successful work therefore represents a considerable achievement, particularly in the field of protein-protein interactions.”

The research leading to the discovery of these compounds is the basis of a collaboration and licensing agreement between the Walter and Eliza Hall Institute, Genentech Inc and Abbott, the leader in Bcl-2 inhibitor development.

Dr Lessene is the second person from the Walter and Eliza Hall Institute to win the Biota Award. Dr Jonathan Baell, also from the Structural Biology Division, received the award in 2004.

Source: Walter and Eliza Hall Institute

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Alzheimer’s Research Provides Potential Treatment for UTI

Last Updated on Monday, 11 January 2010 06:05 Written by Editor Monday, 11 January 2010 06:05

Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” said senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” said co-lead author Jerome S. Pinkner, laboratory manager for Hultgren.

“We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment,” Pinkner added.

Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren said.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

Source: farsnews.com

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iThemba Pharmaceuticals (Pty) Ltd and Pyxis Discovery B.V. Announce Collaborative Agreement to Offer

Last Updated on Monday, 11 January 2010 06:01 Written by Editor Monday, 11 January 2010 06:01

iThemba Pharmaceuticals’ service division and Pyxis Discovery announced today that they have signed a collaborative agreement to jointly market both companies’ services.
Pyxis’s world class computational chemistry and lead discovery expertise will be coupled with iThemba’s service division to provide medicinal and synthetic chemistry support to projects identified through Pyxis’ international client network. iThemba Pharmaceuticals and Pyxis Discovery also announced today that they are entering into a co-marketing agreement to offer virtual libraries which will be exclusively synthesized for clients. Pyxis’s smart approach of designing and selecting compounds facilitates a rapid and efficient lead discovery and library design process and this coupled to iThemba’s expertise in synthetic and medicinal chemistry will provide our customers with a unique service offering opportunity.
“The intellectual and technological support from Pyxis will enhance both of our service offerings,” said Chris Edlin, CSO of iThemba. “Our customers will gain the advantage of our coupled expertise in design, synthesis and medicinal chemistry prowess.”
“Combining the outstanding medicinal chemistry expertise of iThemba with our design approach helps us to provide our clients with a more complete set of services, resulting in swiftly progressing lead discovery and optimization projects.” said Ron van der Valk, Managing Director of Pyxis Discovery. “In addition to this, we hope that our collaboration with iThemba will support their ambition to bring affordable medicines to the less fortunate people in this world.”
About iThemba Pharmaceutical (Pty) Ltd. (http://www.ithembapharma.com)
iThemba Pharmaceuticals (Pty) Ltd., based in Modderfontein, Gauteng, South Africa is founded to discover and develop new and affordable medicines for the diseases of poverty in Africa. The company is funded by the Biotechnology Regional Innovation Centers, LIFElab and BioPAD of the Department of Science and Technology, Government of South Africa. Utilizing leading edge proprietary technology and its expertise in synthetic organic chemistry, iThemba Pharmaceuticals will become the premier research focal point in Africa for infectious diseases including HIV, tuberculosis, malaria and their associated co-infections. The company will create shareholder value by coupling the company’s own drug discovery efforts with collaborative research initiatives and cash-generating contracts to reduce the risks and costs of developing medicines for neglected diseases and low profit-margin markets.
About Pyxis Discovery B.V. (http://www.pyxis-discovery.com)
The ambition of Pyxis Discovery is to be the preferred chemistry service provider for companies that are active in small molecule drug discovery. Pyxis Discovery’s Smart approach of designing and selecting compound libraries facilitates a rapid and efficient lead discovery process, yielding lead compounds with excellent pharmacological profiles. Pyxis Discovery uses proprietary software algorithms for compound design and selection and a Global Supplier Database of nearly all commercially available screening compounds to provide its clients with screening libraries that are tailored to their specific needs. Furthermore, Pyxis Discovery offers high quality compound libraries off the shelf. Pyxis Discovery is headquartered in the Netherlands and has a worldwide presence with also an office in Boston, Massachusetts and representation in Japan.
Source: Pyxis Discovery B.V.

Source: melodika.net

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Drug giant will allow screening of its library of compounds to seek potential treatments for neglected diseases

Last Updated on Monday, 11 January 2010 05:48 Written by Editor Monday, 11 January 2010 05:48

The Drugs for Neglected Diseases initiative (DNDi) has announced an agreement with drug giant Pfizer that will allow it access to the Pfizer library of novel chemical entities, in order to screen it for compounds that could be developed into new treatments for three of the most neglected infectious diseases of poverty: human African trypanosomiasis (HAT), visceral leishmaniasis (VL) and Chagas disease.

Pfizer vice president DrÂ Manos Perros said, â€œWe are expanding our commitment to the fight against tropical diseases by joining forces with DNDi by sharing our collection of chemical compounds and the knowledge and expertise associated with these chemical entitiesâ€. His colleague Dr Sam Azoulay said, â€œWe are confident that the significant resources and expertise that public-private partnerships such as this one bring together, will accelerate and significantly increase the chances of success in the search for effective new drugs against serious infections that disproportionately affect the poorâ€.

Under the agreement, scientists in institutes affiliatedÂ with DNDi will test at least 150,000 compounds in the Pfizer library against Trypanosoma brucei, Leishmania donovani and Trypanosoma cruzi, the kinetoplastid parasites that cause HAT, VL and Chagas disease, respectively. The researchers will seek compounds that show initial activity against the parasites, and thus might form the basis for novel drug discovery programmes to treat the diseases. The screening will be undertaken at the Eskitis Institute for Cell and Molecular Therapies, Griffith University in Brisbane, Australia (for HAT) and the Institut Pasteur Korea (VL and Chagas disease).

â€œThis agreement provides us access to a compound library of novel chemical entities that has never been explored for kinetoplastid diseases. This marks an important step towards DNDiâ€™s objective of building a robust portfolio and to feed the research and development pipeline with new promising compounds,â€ said Dr Shing Chang, R&D director at DNDi. In July this year, DNDi announced a similar agreement with Merck â€“ see press release.

Within the same week as the finalising of its agreement with Pfizer, DNDi also announced it is to receive $15 million of Gates Foundation funding over the next five years, which it will use for the development of fexinidazole, currently the only new drug candidate in clinical development for sleeping sickness â€“ see press release. Further information about DNDi is available here.

Source: tropika.net

Posted under Compound Screening, Drug Development, Press Releases | Comments Off

Ligon Discovery Announces Appointment of Errol B. De Souza as Executive Chairman

Last Updated on Monday, 11 January 2010 05:36 Written by Editor Monday, 11 January 2010 05:36

20-year Industry Veteran Brings Extensive Experience in Drug Discovery and Development

CAMBRIDGE, Mass., Nov. 23 /PRNewswire/ — Ligon Discovery, Inc., which uses proprietary small molecule microarray technology to find drugs against high-value targets, today announced the appointment of pharmaceutical industry veteran Errol B. De Souza as Ligon’s Executive Chairman of the Board.

“I’m very pleased to welcome Errol De Souza as Executive Chairman of the Board,” said Patrick Kleyn, Ligon’s chief executive officer and co-founder. He added, “Errol’s breadth of experience in the life sciences industry — particularly his leadership taking drug candidates from exploratory research through clinical development — will be an asset to Ligon as we advance our current drug discovery campaigns targeting cancer and coagulations disorders, utilizing our proprietary small molecule microarray platform.”

Dr. De Souza commented, “I look forward to chairing Ligon’s Board, and contributing to the forward momentum being built by the company in discovering small molecule drugs against disease targets that others have found intractable. Ligon’s unique and proprietary small molecule microarray technology offers compelling advantages, including broad applicability to all target classes, unprecedented scale of parallel screening, and minimal protein requirements. I believe Ligon has what it takes to leverage this already validated technology.”

Errol B. De Souza, Ph.D. is a seasoned pharma and biotech industry leader with 20 years of experience in senior level Research & Development (R&D) and management positions at Aventis, Hoechst Marion Roussel (HMR), DuPont Merck, Neurocrine Biosciences, Synaptic Pharmaceuticals and Archemix. His R&D experience spans from leading large R&D organizations at DuPont Merck (Director of CNS Diseases Research), HMR (Senior Vice President and Head of Global Lead Generation) with worldwide responsibilities for chemistry, chemical development, biotechnology, high throughput screening and core research functions to Aventis (Senior Vice President and Site Head of US Drug Innovation and Approval) where he had worldwide responsibilities for managing the CNS, Immunology and Inflammatory Diseases pipeline as well as administrative responsibilities for the entire R&D organization in the US including the Global Drug Development Center.

Dr. De Souza’s particular focus has been on the developing innovative approaches to accelerate progression of compounds from the candidate to clinical proof-of-concept stage and beyond through development of biomarker and pharmacogenomic strategies and utilization of imaging techniques. His experience on the biotech side spans from starting companies (Founder, Chief Scientific Officer and Executive Vice President of R&D at Neurocrine), to leading companies (President & CEO of Synaptic Pharmaceuticals and Archemix, Inc) and experience on several Boards of Directors and Scientific Advisory Boards of both public and private companies. In these capacities, he has successfully raised capital in both private and public environments and been involved in multiple collaborations with large pharmaceutical companies.

About Ligon Discovery

Ligon Discovery is a Harvard spinout that leverages a patented platform technology to identify pre-clinical drug candidates. The company’s high-throughput microarray “chip” transforms the speed of the drug discovery process and expands the scope of new drug prospecting to include previously intractable targets. With funding from incTANK Ventures, the team has deployed the SMM technology, originally invented at Harvard University and further developed at the Broad Institute (founded by MIT and Harvard University) in Cambridge, and has established one of the largest small molecule screening capabilities in the industry. Using this facility, Ligon has successfully completed screens in the fields of coagulation and cancer, and is actively pursuing drug discovery in other areas of high unmet medical need. For more information, visit www.ligondiscovery.com.

SOURCE Ligon Discovery, Inc.

Posted under Industry News, Press Releases | Comments Off

University of Minnesota invention will help speed development of drug treatments for heart failure

Last Updated on Monday, 11 January 2010 05:33 Written by Editor Monday, 11 January 2010 05:33

Contacts: Patty Mattern, University News Service, (612) 624-2801, mattern@umn.edu
John Merritt, Office of the Vice President for Research, (612) 624-2609
Stacie Byars, Celladon, (206) 660-2588

MINNEAPOLIS / ST. PAUL (11/23/2009) â€”Research conducted by University of Minnesota scientists, in collaboration with Celladon Corporation, has led to the invention of technology to more rapidly identify compounds for the treatment of heart failure.

Chronic heart failure is an increasingly important health problem. It is the leading medical cause of hospitalization and is expected to result in an estimated direct and indirect cost to the health care system of $37.2 billion in 2009 alone. About 5.7 million people in the United States have heart failure, and it contributes to or causes some 290,000 deaths annually. However, developing new treatments is an extremely costly and time-consuming process, taking nearly a decade to gain regulatory approval and requiring hundreds of millions of dollars.

The technology, developed by the universitys David Thomas and Razvan Cornea and Celladon CorporationsÂ Krisztina Zsebo, allows for increased screening efficiency of compounds capable of disrupting the interactions of proteins implicated in the development of heart failure. Fluorescence resonance energy transfer (FRET) is used to measure disruption of the calcium regulatory system, which has long been implicated in cardiovascular disease. This will provide key information on a particular drugs likelihood of success early in the screening process, since compounds that decrease FRET are good candidates for further development.

“Dr. Cornea and I, along with our students, have worked for more than a decade developing methods for preparing membranes from purified components, and using FRET to detect changes in protein interactions,” Thomas said. “Scientists from Celladon saw the potential for drug discovery, and this resulted in a breakthrough that has added an exciting new dimension to our research program.”

The high-throughput assay, developed by the university team, is based on a reconstituted membrane system composed of purified lipid and protein components. This technique is especially important because the interactions of integral membrane proteins are more complex than soluble proteins, making it very difficult to produce a synthetic system that recapitulates the cellular interactions in a large-scale and reproducible manner.

Celladon, based in La Jolla, Calif., has acquired an exclusive license for the technology from the University of Minnesota for the development of molecular therapies for cardiovascular diseases. Celladon also provided funding for the research that allowed Thomas to further refine the assay.

“This technology is very important to the efficient selection and advancement of compounds with the potential to increase cardiac contractility and potentially accelerates product opportunities that will ultimately benefit patients and development partners alike,” said Krisztina M. Zsebo, Ph.D., president and chief executive officer of Celladon Corporation. “Celladon’s investigation and development of first-in-class CDN small molecules as intravenous and oral drugs for the treatment of acute and chronic heart failure sets us apart in the cardiovascular field and presents multiple partnering opportunities.”

Source: umn.edu

Posted under Cell-based Assays, Compound Screening, Press Releases | Comments Off

JAXâ€“West Helps Search for Compounds That Radically Extend Lifespan

Last Updated on Monday, 11 January 2010 05:30 Written by Editor Monday, 11 January 2010 05:30

In 2004, Avi Kremer, a 29-year old Harvard Business School student, was diagnosed with ALS. Aviâ€™s doctors told him there was nothing that modern medicine could do for him. In response, he and fellow students founded Prize4Life, Inc. , a non-profit organization dedicated to accelerating research for treating and curing ALS by using the leverage of large inducement prizes. In 2006, Prize4Life opened the â€œALS Biomarker Challenge,â€ offering a $1 million prize to a researcher who could find a biomarker that would reliably measure disease progress in ALS patients. A year ago, it established the â€œAvi Kremer ALS Treatment Prize,â€ a $1 million award for finding a treatment candidate that reliably and significantly increases the lifespan of ALS mouse models. Competing teams are actively pursuing several approaches, including therapies to replace damaged cells, protein-based therapeutics, and small molecule drugs that interfere with ALS-implicated pathways. Competition for both prizes is open to all interested researchers. Both prizes have attracted research teams from industry and academia from around the world.

The SOD1 Mouse

Three percent of ALS cases are associated with mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) gene, the first gene associated with ALS. With so little known about the genetics of ALS, research so far has concentrated on the pathogenesis of SOD1 mutations in laboratory mice. To provide researchers with the most widely used ALS mouse models available for preclinical drug testing, Prize4Life has partnered with The Jackson Laboratory (JAX). The models, popularly known as SOD1 mice, are distributed from dedicated supply colonies maintained by JAXÂ® Breeding Services. JAX currently distributes 12 different SOD1 models – with different forms of the SOD1 mutation and on different genetic backgrounds. Among the most widely used of these models is JAXÂ® Mice strain B6SJL-Tg(SOD1*G93A)1Gur/J (002726). Like several other SOD1 models, this one has a high copy number of the mutant human superoxide dismutase 1 (SOD1) transgene, which contains the Gly93–>Ala (G93A) substitution. The mutation underlies the most studied form of inherited ALS in humans. The mice lose motor neurons in the spinal cord, become paralyzed in one or more limbs, and die by four to five months. These phenotypes closely model those of human ALS (Gurney et al. 1994). As noted by Dr. Tom Maniatis, Chair of Columbia Universityâ€™s Biochemistry & Molecular Biophysics Program, a prominent ALS researcher, and a member of Prize4Life’s Scientific Advisory Board, â€œAn effective treatment for ALS is desperately needed, and the existing [SOD1] mouse model is the primary gateway to clinical trialsâ€ (CheckOrphan 2009).

SOD1 Mice Need Special Care

Many of the initial studies conducted with Tg(SOD1*G93A)1Gur/J mice have provided a wealth of information and insight on how to best use them in preclinical trials. However, like other highly expressed transgenes, the G93A transgene can spontaneously lose copy number, which can greatly confound experimental results. Therefore, the mice need to be handled carefully. When Prize4Life approached JAX to establish a dedicated supply for their researchers, Dr. Melanie Leitner (Chief Operating Officer and Chief Scientific Officer for Prize4Life), Dr. A. Sheila Menzies (Scientific Program Officer for Prize4Life), and Dr. Cathleen Lutz (Associate Director for Genetic Resource Science at JAX) produced a companion set of informational materials entitled â€œWorking with ALS Miceâ€. The materials are available at www.jax.org/jaxmice/literature/factsheet/working_with_ALS_mice.pdf.

â€œPrize4Life spearheaded this effort,â€ say Lutz. â€œItâ€™s really targeted to those investigators who are new to the field of ALS and who are working with the SOD1 mice and designing their preclinical trials. The scientific community has learned a great deal about how to work with these mice over the years. Itâ€™s important to make that information more widely known so that valuable time and resources arenâ€™t wasted by repeating past mistakes.â€

If Prize4life succeeds in its goal of bridging the critical steps between academic discovery and therapy in the clinic, it could have major implications for ALS patients and for any group trying to solve a biomedical problem. Interested researchers can learn more at www.prize4life.org.

References

CheckOrphan. 2009. Prize4Life marks one-year anniversary of Avi Kremer ALS Treatment Prize. http://www.checkorphan.org/news/prize4life_marks_one_year_anniversary_avi_kremer_als_treatment_prize. October 13, 2009.

Gurney ME, Pu H, Chiu AY, Daly Canto MC, et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772-5.

Source: animallab.com

Posted under Discoveries, Innovations and Patents, Drug Development, Press Releases, R & D | Comments Off

Rising to the Challenge in R&D

Last Updated on Monday, 11 January 2010 05:22 Written by Editor Monday, 11 January 2010 05:22

There has long been a consensus within the pharmaceutical industry that innovation and productivity is a critical focus. Nevertheless, the number of new molecular entities (NMEs) approved each year by FDA shows that industry has not been improving its output, despite progress in development and implementation of enabling technologies.

Over the past 20 years there has actually been a decline in NMEs approved by FDA. Furthermore, many of the NMEs approved are â€œme-tooâ€ molecules for disease states where first-in-class drugs are already on the market. Granted, there are other reasons for the dearth of product innovationâ€”including regulatory issues, an increasing focus on short-term returns by some shareholders, and corporate restructuringâ€”but the fact remains that pharmaceutical companies need NMEs with novel mechanisms and better safety and efficacy than offered in currently available drugs. Clearly, new chemistry allowing access to well known targets that have been intractable to older chemistries could provide a kick-start to the malaise in drug discovery.

A New Kind of Chemistry: Allosteric Modulation
Even as biologics, RNAi, and gene and cell therapies may provide value to patients in the short-to-medium term, small molecule drugs may one day offer patients many of the same benefits in a format that is more patient friendly (i.e. oral administration) and, potentially, with easier manufacturing and/or lower costs compared to non-pharmaceutical drugs. Allosteric modulators are an emerging class of orally available small molecule drugs that may have multiple advantages compared to traditional orthosteric drugs, including biologics.

Allosteric modulators have been shown to achieve greater selectivity, successfully modulating previously intractable therapeutic targets. In addition, orally available small molecule allosteric modulators have been discovered for targets for which only injectable biologic drugs are available. It is easier to achieve selectivity when targeting more heterogeneous allosteric binding sites on targets with therapeutic potentialâ€”such as G-Protein Coupled Receptors (GPCRs) and cytokine receptorsâ€”than an â€œactive site,â€ which is often highly conserved across multiple related receptors.

Simply put, the active site on receptors acts as a switch that controls turning receptor signaling. Unlike orthosteric drugs, which turn receptors completely on or off, allosteric modulators act like a dimmer switch to mediate the intensity and frequency of receptor signaling. However, the trigger for signaling remains under the control of the endogenous ligand, which binds the target according to the physiological rhythm determined by the body. In many cases, allowing the body to retain control over initiating signaling while simply increasing or decreasing the amplitude of that signaling may offer a competitive advantage over other approaches. Although it has often been attempted with orthosteric drugs, comparable functional control over receptor signaling cannot be achieved simply by modifying the dose or delivery of orthosteric drugs.

Key Advantages of Allosteric Modulation

Because they do not compete for the endogenous ligand binding site and exert their effects even in the presence of endogenous ligands, lower doses of allosteric modulators may have greater potency than orthosteric molecules with similar affinity for the same target. Lower dosing often leads to fewer side effects.
Allosteric modulators can be devoid of activity in the absence of endogenous ligands, offering a less disruptive way to influence the functioning of biological systems and therefore could lead to greater safety and fewer tolerability issues.
Because they bind on a distinct site, it is possible to create new chemical entities with unfettered intellectual property that re-address well validated GPCR targets for which there are marketed products. In such cases, the goal would be that the allosteric mechanism offer clear differentiation in terms of efficacy and/or side effects.
It follows that highly selective allosteric modulators can be made for targets where it has been difficult to make selective orthosteric modulators. For example, orally available small molecule allosteric modulators against GLP-1 and FSH receptorsâ€”for which only peptide, protein or hormonal therapies are availableâ€”have been discovered.
Because they bind at a separate site, it is possible to combine allosteric modulators with orthosteric drugs. For example, a positive allosteric modulator, or PAM, could be used to potentiate an orthosteric agonist. This could alleviate side effects associated with off-target effects seen at high doses of some orthosteric drugs or simply reduce cost of goods for other orthosteric drugs, especially with biologics.

History of Allosteric Modulators
The concept of allosteric modulation is not new; scientists have been discussing it since the first half of the 20th century, and some suspected such a mechanism even earlier. In the 1960s, Roche introduced the tranquilizer Valium, which later was discovered to act by allosteric modulation of gamma-aminobutyric acid (GABA) receptors. More recent allosteric modulators include Sensipar (cinacalcet, from Amgen), a calcium-sensing receptor PAM, and Selzentry (maraviroc, from Pfizer), a CCR5 NAM.

But these first-to-market drugs were found more through serendipity than through focused searches for allosteric modulators. Indeed, the industrialization of allosteric drug discovery is something that many pharma companies and venture capitalists have shied away from due to the risks and the magnitude of investment.

The search for new drugs has long focused on GPCRs, but of roughly 850 known GPCRs less than 200 have been drugged. Compounds identified through screening have typically worked at the orthosteric site, but after finding the so-called â€œlow hanging fruit,â€ this approach delivers fewer and fewer hits. In the late 1990s, researchers made some breakthroughs, identifying mGluR selective ligands that didnâ€™t bind to the active sites on glutamate receptors, including allosteric modulators, targeting the metabotropic glutamate receptor 5 (mGluR5), which was discovered by researchers at SIBIA Neurosciences in collaboration with Novartis.

The goal soon became finding similar allosteric drugs; and for this, a new type of screening assay was needed. In the mid-1990s, screening assays evolved to include biological function. When the resulting compounds started to show different types of effects on the receptor, researchers concluded allosteric modulation may be playing a role.

In 2001, Vincent Mutel, CEO of Addex Pharmaceuticals, was a pharmacologist at Roche. Almost by chance, he and his colleagues discovered an allosteric molecule that enhanced the activity of the metabotropic glutamate receptor 1 (mGluR1). This glutamate receptor subtype was not tied to any particular disease, but the finding convinced Mutel that allosteric molecules could enhance an effect as well as block.

Addex was founded in 2002 and initial discovery work focused on targeting mGluR5 for addiction. As mGluRs had been intractable to orthosteric chemistry, Dr. Mutel and his team developed biological screening tools that would detect allosteric modulators of mGluR5 and other mGluR subtypes. It turned out that the tools developed could be adapted to almost any GPCR, and eventually to other types of receptors, like cytokine receptors. GPCRs are the targets of more than 30 percent of all medicines currently on the market . The company has disclosed discovering receptors in all three GPCR families and, more recently advances in the discovery of small molecules targeting receptors such as TNF-R1, IL-1R1, GIPR and GLP-1R, targets that have previously only been addressed by injectable protein or peptide therapeutics .

Future of Allosteric Modulators
The role of specific receptor sub-types has been elucidated in many diseases; however, in many cases, it has been challenging to develop sub-type specific drugs. These cases are the low hanging fruit for allosteric modulators. For example, metabotropic glutamate receptor 5 (mGluR5) has been implicated and clinically or preclinically validated in multiple diseases for more than two decades. But it took Big Pharma more than 20 years after the cloning of the mGluR5 receptor to identify and begin testing selective molecules against this high value target. In the end most if not all the molecules targeting mGluR5 are allosteric modulators. These molecules have progressed into the clinic and are now showing efficacy in humans in a variety of indications.

Addexâ€™s lead compound ADX10059, a negative allosteric modulator of mGluR5, has shown efficacy in separate early Phase II studies for gastroesophageal reflux disease (GERD) and migraines. Clinical and preclinical data from Addex and other groups suggest that the product also has potential in Parkinsonâ€™s disease, and certain chronic forms of anxiety and depression. Other companies already are working on mGluR5 inhibitors to treat Parkinsonâ€™s disease, Fragile X, and neuropathic pain.

The allosteric drugs also could be combined with conventional orthosteric drugs against the same target to maximize the efficacy of the orthosteric and/or allow use of lower doses. This could be a desirable strategy to minimize dose-related, off-target side effects associated with the orthosteric product while potentially also reducing the cost of goods (especially if it is a biologic).

Allosteric modulators may become a life-cycle management strategy for biologics drugs. In the future, orally available small molecule allosteric modulator may be able to replace or complement many biologic drugs. The cost of a prescription allosteric modulator could, in some cases, obviate the opportunity for bio-generic competition while preserving the profit margin of the prescription biologic.

Allosteric drug discovery and development has only just begun. Many skeptics are being won over and it is beginning to become a mainstream approach. With more than 70,000 potential allosteric modulators in its unique biased library and a growing number of proprietary biological screening tools, Addex is leading the field. Its growing pipeline and partnerships serve as increasingly irrefutable validations. The approach, however, is much bigger than one company, with many in the industry predicting that allosteric modulation will become a new therapeutic class in the medical armamentarium.
Source: findpharma.com

Posted under Drug Development, New Drugs, Press Releases, Reports | Comments Off

Caprotec bioanalytics Opens U.S. Subsidiary to Exploit Capture Compound Mass Spec

Last Updated on Monday, 11 January 2010 04:22 Written by Editor Monday, 11 January 2010 04:22

Berlin-based Caprotec bioanalytics opened a U.S. subsidiary in Burlington, MA. The U.S. business will be responsible for North American sales, marketing, and support for the companyâ€™s Capture Compound Mass Spectrometry (CCMS) technology and related products.

Christian Jurinke, Ph.D., Caprotecâ€™s head of product commercialization and distribution, has been appointed president of the new U.S. subsidiary. The business is also partnering with Genovative Solutions to help boost sales of CCMS products and services in North America.

The CCMS technology has been developed to target, capture, and isolate selected proteins, including membrane proteins, out of any complex biological sample, based on their functionality.

The approach uses synthetic Capture Compound molecules to interrogate native proteins, including lipophilic membrane proteins, in virtually any biological sample. Caprotec is commercializing CCMS through preconfigured caproKitsâ„¢, and through contract services based on already available Capture Compounds. The company also works in collaboration with companies and researchers in areas including drug interaction protein profiling, drug target identification, and evaluating drug mode of action and off-target side effects.

The first two caproKits, SAH caproKit, and cAMP caproKit, were launched in January. CaproKits are currently available for protein kinases, cAMP- and cGMP-binding proteins, methyl transferases, and metalloproteases. New kits are also constantly being developed.

The CCMS process can be described as a homogeneous reverse high-throughput screening, Caprotec explains. In essence, the proteome is treated as a library and screened for individual proteins that interact with the highly selective Capture Compounds. The features of CCMS hinge on the multifunctionality of these synthetic Capture Compound molecules. Not only do Capture Compounds function selectively, e.g., for an enzyme substrate/inhibitor, a co-factor or drug candidate), but they also have a reactivity function, to covalently bind the protein target. A sorting function then pulls the Capture Compound-protein-complex directly out of cell lysates.

Source: genengnews.com

Posted under Drug Development, Press Releases | Comments Off

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Alzheimer’s Study Leads To Better Drug For Infections

University of California, San Francisco, Researcher Receives ASBMB-Merck Award

Techne accelerates sample concentration

Potent Novel Tool For Combating Autoimmune Diseases And Leukemia

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Androgen insensitivity syndrome

Superandrogen

2009: The Year That Was For Pfizer

Model for powerful flu fighters from existing drugs

Therasis Obtains $12 Million From Tilocor in Series A Round

InformexUSA 2010

Forma Therapeutics raises $25.5M in Series B round

Anti-cancer compound wins scientist Biota Award

Alzheimer’s Research Provides Potential Treatment for UTI

iThemba Pharmaceuticals (Pty) Ltd and Pyxis Discovery B.V. Announce Collaborative Agreement to Offer

Drug giant will allow screening of its library of compounds to seek potential treatments for neglected diseases

Ligon Discovery Announces Appointment of Errol B. De Souza as Executive Chairman

20-year Industry Veteran Brings Extensive Experience in Drug Discovery and Development

University of Minnesota invention will help speed development of drug treatments for heart failure

JAXâ€“West Helps Search for Compounds That Radically Extend Lifespan

Rising to the Challenge in R&D

Caprotec bioanalytics Opens U.S. Subsidiary to Exploit Capture Compound Mass Spec

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