Tuesday, April 14, 2009
FDA Staff Asks President to Straighten Up Agency
Update on Ipsen's botulinum toxin type A Product Regulatory Review Status in the US
Pharmacyclics Initiates Phase 1 Clinical Trial of Novel Oral Btk Inhibitor for Refractory B-cell Non-Hodgkin's Lymphoma
Bruton's tyrosine kinase is the gene that is disrupted in the human disease X-linked agammaglobulenemia (XLA). Patients with XLA are devoid of mature B-lymphocytes and immunoglobulins in the bloodstream, but are otherwise healthy. XLA thus provides strong clinical rationale for development of a novel therapeutic drug targeting Btk for safe inhibition of B-cell mediated diseases. In preclinical studies, PCI-32765 has the remarkable ability to selectively inhibit human B-cell activation without effecting T cells. Strong preclinical validation of Btk as a target in lymphoma was generated using PCI-32765 in a mouse model of B-cell receptor-driven lymphoma and in spontaneous B-cell lymphoma in companion canines. These studies will be reported in presentations at the 2009 AACR annual meeting in
"This is a very selective compound for B-cells, and it could represent an important alternative to rituximab therapy for the treatment of B-cell NHL. Other obvious applications include autoimmune disorders such as rheumatoid arthritis and lupus, and Pharmacyclics also has strong preclinical efficacy with PCI-32765 in these disease models," said Dr.
"Despite recent success with biologics in the treatment of B-cell NHL, there is still a large group of patients that do not respond to therapy or who experience recurrence," said
This Phase 1 study is evaluating the safety and pharmacokinetics of PCI-32765 in patients with refractory B-cell non-Hodgkin's lymphoma at
Pharmacyclics Btk Presentations at AACR
#1984 Btk is a Novel Therapeutic Target to Treat Large B-cell Lymphomas Ryan M. Young,
#3740 A Clinical Trial of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Naturally Occurring Canine Lymphoma.
About Pharmacyclics' Btk Inhibitor Program
PCI-32765 is currently targeted for oncology while other Pharmacyclics Btk inhibitors are being developed for application to autoimmune and inflammatory diseases. Bruton's tyrosine kinase is a critical enzyme involved in B-cell activation and function, and inhibition may be useful in the treatment of a number of immune mediated diseases. B-cells are a type of white blood cell that normally play an important role in the body's immune response. However, when B-cells are overactive, the immune system produces inflammatory cells and antibodies that begin to attack the body's own tissue, leading to autoimmune disorders. Also many lymphomas are caused by uncontrolled growth of B-cells where activation of the B-cell receptor and Btk signaling are thought to play important roles.
In addition to being studied in a Phase 1 trial for refractory B-cell non- Hodgkin lymphoma, PCI-32765 has been evaluated in preclinical studies in collagen-induced arthritis, an established animal model for RA. In these studies, PCI-32765 dramatically reduced inflammation and induced regression of established disease as reported at the Federation of Clinical Immunology Societies (FOCIS) 2008 annual meeting .
Therapeutic effect of imatinib improved with addition of chloroquine
(PHILADELPHIA) The therapeutic effects of the blockbuster leukemia drug imatinib may be enhanced when given along with a drug that inhibits a cell process called autophagy, researchers from the Kimmel Cancer Center at Jefferson reported in the Journal of Clinical Investigation.
The cell-death effect of imatinib (Gleevec) was potentiated when chloroquine, an autophagy inhibitor, was given with imatinib for the in vitro treatment of chronic myeloid leukemia (CML) cells including the CML stem cells, according to Bruno Calabretta, M.D., Ph.D., professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University.
Autophagy is a process that allows cells to adapt to environmental stresses, and enables drug-treated CML cells to escape cell death. Imatinib is a tyrosine kinase inhibitor that suppresses proliferation and induces death of the malignant cells that cause CML. However, additional effects of the drug have not been studied in detail, according to Dr. Calabretta.
In this study, Dr. Calabretta's team, along with Dr. Paolo Salomoni's team from the MRC Toxicology Unit at the University of Leicester in the United Kingdom, found that imatinib induces autophagy in CML stem cells that overexpress a protein called p210BCR/ABL. Stem cells that express this protein have been historically resistant to imatinib and also to second-generation tyrosine kinase inhibitors, including dasatinib, nilotinib and bosutinib.
The autophagy process allows stem cells to survive treatment with imatinib, and continue to survive. The researchers used chloroquine to see if it would have an effect on imatinib treatment. The dual treatment with imatinib and chloroquine eliminated most CML stem cells. Also, imatinib-induced cell death was significantly increased in mice inoculated with p210BCR/ABL-expressing cells.
"Imatinib's primary effect is inhibiting the proliferation of CML cells, but the frequency of resistance increases in advanced stages of the disease," Dr. Calabretta said. "There is a need to develop new therapeutic approaches that, in combination with tyrosine kinase inhibitors, eliminate CML stem cells that escape imatinib treatment. We show that imatinib induces autophagy, which enables these cells to survive and eventually resume proliferation. We also show that chloroquine, an autophagy inhibitor, combined with imatinib actually appears to potentiate imatinib-induced cell death."
Enhancing the effects of the drug used to treat chronic myeloid leukemia
Individuals with chronic myeloid leukemia (CML) are first treated with a drug known as imatinib mesylate. Although very effective, as the disease progresses it often becomes resistant to the drug. However, a team of researchers, at the University of Leicester, United Kingdom, and Thomas Jefferson University, Philadelphia, has identified a class of drugs that might enhance the therapeutic effects of imatinib mesylate and other drugs that target the same molecule.
The team, led by Paolo Salomoni and Bruno Calabretta, observed that for several different CML cell lines and primary cells, although imatinib mesylate killed the majority of cells, a marked proportion underwent a process known as autophagy. Consistent with studies indicating that the induction of autophagy can provide a mechanism of cellular survival, suppression of autophagy using either drugs or RNA interference enhanced imatinib mesylate–induced death of CML cell lines, primary CML cells, and CML stem cells. The authors therefore suggest that inhibitors of autophagy might be used with imatinib mesylate or other drugs that target the same molecule to enhance their therapeutic benefits.
Monday, April 13, 2009
Medtronic Completes Acquisition of CoreValve Inc
Epilepsy Pipeline Conference 2009 to Showcase Cutting-Edge Therapies in Development and Advances in the Treatment of Epilepsy
MIDDLEBURG, Va.--(BUSINESS WIRE)--The Epilepsy Therapy Project today announced that more than 25 emerging companies as well as leading biotechnology and pharmaceutical investors and industry executives will gather to focus on preclinical and clinical development strategies and opportunities at the Epilepsy Pipeline Conference 2009. The one-day Epilepsy Pipeline Conference 2009 will showcase the most innovative therapeutic approaches currently in development for the treatment of epilepsy. The conference will take place Friday, April 17, 2009 at the Biltmore Hotel in Coral Gables, Florida, in conjunction with the Antiepileptic Drug Trials X (AED-X) conference.
“With more than three million patients in the US alone, epilepsy represents a huge and significantly unmet medical need. We are excited to see such a high caliber group of scientific entrepreneurs presenting the latest insights and approaches to addressing epilepsy, as well as other central nervous system disorders,” said Joyce Cramer, President of Epilepsy Therapy Project. “In addition to our commitment to funding clinical research, the Epilepsy Therapy Project plays a critical role in bringing together scientific entrepreneurs with venture capital and public equity investors and pharmaceutical industry partners. Through the Epilepsy Pipeline Conference 2009 we are creating a forum to drive innovation in the discovery and development of new treatments that we hope will ultimately eradicate seizures in the next decade.”
Pipeline conference attendees will hear the latest insights from research, clinical and industry leaders, supporting informed decisions about investment in epilepsy therapy development and broader central nervous system (CNS) therapeutic areas. Investors and industry business development executives are encouraged to attend.
"With well-characterized mechanisms, therapeutic approaches, functional models and defined clinical endpoints, epilepsy is gaining recognition as an excellent starting point for companies seeking to develop new CNS diagnostics and therapeutics," said Omar Amirana, MD, Partner at Oxford Bioscience Partners. "Forums such as this provide investors, research experts and industry leaders with an opportunity to understand the major scientific and clinical advances taking place in CNS and help optimize our collective investments in future therapies."
Presenting companies at the one-day conference include: Marinus Pharmaceuticals, Sepracor, Valeant Pharmaceuticals, Icagen, NeuroTherapeutics Pharma, Neuropace and SierraNeuro, among others. In addition, the conference will feature a dynamic panel discussion between private and public investors as well as commercial business development executives on financing new epilepsy and CNS therapies.
Will Emerging Agents Disrupt the Psoriatic Arthritis Market?
DUBLIN, Ireland--(BUSINESS WIRE)--Research and Markets (http://www.researchandmarkets.com/research/e51325/will_emerging_agen) has announced the addition of Decision Resources, Inc.'s new report "Will Emerging Agents Disrupt the Psoriatic Arthritis Market?" to their offering.
Surveyed rheumatologists are open to prescribing emerging agents for psoriatic arthritis (PsA) patients upon approval. That is good news for the PsA patients who fail to respond to TNF-a inhibitors; treatment options are limited for these patients. Availability of the TNF-a inhibitors vastly improved treatment of the disease and effected a sweeping change in the approach to managing PsA. Several emerging agents offer novel approaches to treating PsA—will they prompt another shift in management of this chronic and debilitating disease?
Get the Answers You Need to Shape Your Strategy
- PsA a chronic, debilitating disease that is both - underdiagnosed and undertreated. What are the symptoms of PsA? How is the disease diagnosed? What are the risk factors for the disease? How many people in the United States and Europe have PsA? How will this population grow over the next ten years?
- TNF-a inhibitors were the first agents to receive approval for PsA. How are TNF-a inhibitors incorporated into rheumatologists' treatment choices? How will emerging treatments compete with TNF-a inhibitors?
- Because of the high cost and increased use of TNF-a inhibitors, the PsA market has experienced strong growth over the past few years. Will the PsA market continue to grow? How will emerging agents perform in the market?
Scope
- Primary research: survey of U.S. rheumatologists.
- Overview of PsA: etiology, symptoms, and diagnosis.
- Current treatments: nonsteroidal anti-inflammatory agents, conventional diseasemodifying antirheumatic drugs, and TNF-a inhibitors.
- Epidemiology: prevalent cases of PsA in the United States, France, Germany, Italy, Spain, and the United Kingdom.
- Emerging agents: Centocor/Schering-Plough/Janssen/Mitsubishi Tanabe's golimumab; Bristol-Myers Squibb's Orencia; Centocor/Medarex's Stelara; Celgene's apremilast; and Novartis's AIN-457.
- Market overview: 2007 PsA market; outlook for current and emerging agents.
Major Pharmaceutical Company to Utilize Vemics iMedicor Medical Communications Portal
NANUET, N.Y.--(BUSINESS WIRE)--Vemics, Inc. (OTCBB: VMCI) today announced that its iMedicor HIPAA compliant medical communications portal will be utilized by a major pharmaceutical company in a specialized marketing program to commence June 1.
This company, which is traded on the New York Stock Exchange, will use iMedicor to distribute customized marketing messages on a pain management product to a targeted list of over 100,000 physician specialists nationwide. These messages will comprise product-specific educational resources and will be transmitted in real time on a 24/7 basis. Doctors receiving these messages may subsequently utilize iMedicor to order product samples, set appointments with pharma sales representatives and communicate directly with pharma medical science liaisons.
In return for use of iMedicor, Vemics will receive a start-up fee plus recurring fees for the transactions listed above.
The iMedicor program is expected to significantly reduce the need for live visits by pharmaceutical sales reps to physicians’ offices, and broaden the scope and quality of communications between pharmaceutical companies and physicians. In addition, iMedicor estimates its system will slash the cost of in-person marketing by as much as 80 percent per encounter and create a higher return on investment for the pharma.
The program’s messages will be created and managed by pharmaceutical marketing firm Franklyn Ideas, which currently serves some of the world’s largest pharmas and which has engineered marketing programs for hundreds of brands.
Vemics chief executive, Fred Zolla, said, “Today’s announcement marks a milestone in our drive to provide pharmaceutical companies with state-of-the art technology delivering targeted marketing messages proven to elicit the highest rate of response among healthcare providers.
“With the pharmaceutical marketing expertise of Franklyn Ideas, we anticipate making this program an unqualified success—and one that could encourage other pharmas to follow suit.”
For cancer cells, genetics alone is poor indicator for drug response
Same with cells.
Researchers tend to identify characteristics of particular cells by looking at millions at a time. As a result, they'll find that, say, "group A" responds very well to a particular cancer treatment, whereas "group B" does not. They will then often compare group A to group B to find out why.
But often ignored is that not every cell in either group behaves in ways that the aggregate indicates. In a group of cells shown to be vulnerable to a particular cancer treatment, perhaps 10 percent resist it while 90 percent succumb. While researchers have offered various explanations for this, few have studied it.
Now a group of scientists in the lab of Harvard Medical School Professor of Systems Biology Peter Sorger have studied such "outlier" cells in the context of a new and highly touted cancer drug. They have found that vastly disparate reactions occur within genetically homogeneous cell groups. These discrepancies result from protein levels that vary from cell to cell, even among cells that are identical genetic twins. What's more, these protein levels and their subsequent traits can be passed down to daughter cells—a heritability that has nothing to do with genetics.
"Genetics are permanently heritable, while these protein levels are temporarily heritable," says Sorger. "But this temporary inheritance can make all the difference in the world when it comes to the effectiveness of certain medications."
These findings are published April 12 online in Nature.
In order to investigate this disparate behavior among cells, graduate student Sabrina Spencer and postdoctoral researcher Suzanne Gaudet, both in Sorger's lab, looked at a molecule called TRAIL, a protein that causes cells to, literally, commit suicide—a process scientists call apoptosis. While TRAIL is a natural cell product, drug makers have been investigating ways to harness its power so that it can directly target cancer cells.
While TRAIL continues to be a promising drug candidate, its success rate isn't 100 percent, and the researchers wanted to figure out why.
The researchers took both cancerous and non-cancerous cells and exposed them to varying doses of TRAIL. Although these cell lines were known to be vulnerable to the molecule, a fraction always managed to survive.
The researchers noticed that when this outlier group was isolated and once again exposed to TRAIL, the cells and their immediate progeny continued to remain highly resistant for a short time. An immediate explanation might be that this group had developed some sort of genetic defense. However, when this new "resistant" group was given several days to reproduce, the pattern soon reset to the original: 90 percent died, ten percent survived.
"We knew that there were clearly factors at work here that were not genetic," says Spencer. "Genetic resistance would remain uniform in subsequent generations. But the factors at work here were clearly more dynamic."
Using a variety of imaging techniques, the researchers soon discovered that even though these cells were genetically identical —the same cell in the same tissue doing the same thing, the actual numbers of proteins in each cell varied. Specifically, proteins involved in the cell-suicide mechanism triggered by TRAIL were affected. These protein levels altered the dynamics of the entire mechanism, sometimes making cells, for all intents and purposes, immune to TRAIL. While these protein levels were initially passed on to progeny, the heritability was transient. The scientists describe it as an extra layer of inheritance, one that is superimposed onto genetic inheritance.
As for what actually causes these protein levels to vary between identical cells, the researchers cited a simple explanation: It's completely random.
"For decades biologists have had this notion that cells produce proteins in orderly, uniform ways, like an assembly line, but they don't," says Sorger. "Rather, cells produce proteins in fits and starts, and the timing and degree varies from one cell to the next—even cells that are identical in every way. This randomness is something that we're just beginning to appreciate."
These findings also offer an alternative to the cancer stem-cell hypothesis. For that, scientists have posited that certain cancers survive standard treatments because a population of tumor-specific stem cells evades chemotherapy or radiation. This paper, however, offers an alternative explanation, namely, that purely through chance, certain cells produce quantities of proteins that fundamentally alter the cell's response to treatment.
Ultimately, Sorger and his group think that this new insight will make it possible to design anti-cancer treatments that are more effective than those available today.
Pfizer To Make A Tender Offer To Increase Stake In Pfizer Limited
Successful completion of this offer, assuming full acceptance, would raise the indirect stake of Pfizer Inc in Pfizer Limited to 75% from the current level of 41.23%. The offer will represent a total value of up to Rs. 6.8 billion, or approximately USD 136 million.
A public announcement will be issued in India as required by the SEBI (Substantial Acquisition of Shares and Takeovers) Regulations, 1997 (“SEBI Regulations, 1997”). The offer for these shares, which are traded on the Bombay Stock Exchange Limited (“BSE”) and the National Stock Exchange of India Limited (“NSE”), is expected to open in June 2009 and is subject to regulatory approvals. The open offer will be managed by HSBC Securities and Capital Markets (India) Private Limited.
The offer will be made at a premium of 8.6% to the closing share price of Rs. 621.55 of Pfizer Limited on April 9, 2009, on the NSE (equivalent premium of 8.3% to the closing price of Rs. 623.00 on the BSE), which was the last trading day before the announcement of the tender offer. It will also represent a premium of 22.2% over Pfizer Limited’s average share price during the 30 days ending April 9, 2009, on the NSE (equivalent premium of 22.3% over the average share price during the 30 days ending April 9, 2009, on the BSE) and a premium of 45.2% over the requisite price determined in accordance with SEBI Regulations, 1997.
Saturday, April 11, 2009
FDA approves Novartis' malaria drug Coartem
The US Food and Drug Administration has approved Coartem (artemether and lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilogrammes due to plasmodium falciparum, the most dangerous form of the disease. The approval was expected after an FDA advisory panel declared the treatment to be safe and effective in December.
Edward Cox, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said that because of concerns about resistance with currently available therapy, “it will benefit patients to have another treatment option for malaria”. Novartis says that Coartem is a highly-effective three-day therapy with cure rates of over 96%, “even in areas of multi-drug resistance”.
Novartis chief executive Daniel Vasella said that with a growing number of malaria cases in the USA due to rising travel, it is important to make artemisinin-based combination treatment such as Coartem, the most effective therapy for malaria, available to American patients as well."
Fighting malaria “is very much in America's interest and ACTs such as Coartem are important weapons against this infectious disease," said Tim Ziemer, the US government’s malaria coordinator. The Swiss major, which noted that it supplies Coartem for public sector use in Africa without profit, has to date provided more than 235 million treatments, which have helped save an estimated 600,000 lives, mostly children.
Sanofi to buy Brazil’s Medley for 500 million euros
The French firm is going to pay 1.5 billion reals (around 500 million euros) for Medley, which is Brazil’s third-largest pharmaceutical company and number one generics group, with annual sales of about 153 million euros, The deal will be completed during the second quarter.
Family-owned Sao Paulo-based Medley sells 17 of the 20 top generics in Brazil, and Sanofi noted that it employs nearly 1,550 “collaborators”, which includes a sales force of 500. The Paris-headquartered group added that the acquisition will reinforce its number one ranking among pharmaceutical companies in Brazil, with a 12% market share and make it the leading player in the field of generics in Latin America.
Sanofi noted that the Medley purchase “carries on with its strategy to build-up on growth platforms, accelerate sales and further extend its pharmaceutical portfolio in emerging markets”.
The deal comes a week after it acquired Mexican generics firm Laboratorios Kendrick. Financial details of the Kendrick purchase were not disclosed, but sales last year reached 500 million pesos, about 26 million euros. Generics is an area that Sanofi is clearly determined to expand in, having acquired the Czech firm Zentiva at the end of February for 1.8 billion euros.
A number of observers believe that Sanofi’s spending will not stop there. Rumours are doing the rounds that a bid will be forthcoming for Solvay’s pharmaceutical business, while Sanofi’s name has been linked as a possible suitor for Biogen Idec.
the leading pharmaceutical companies in the Philippines
How to get started in the pharmaceutical sales industry
Friday, April 10, 2009
Amgen Cuts 100 Jobs at Washington Manufacturing Plant
SEATTLE --An Amgen Inc. spokeswoman confirms that the drugmaker is cutting 100 jobs at its clinical drug manufacturing site in the Seattle suburb of Bothell, Wash.
Carol Pawlak says the cutbacks are not part of any larger companywide reductions. The biotechnology company has 17,000 employees worldwide.
Pawlak said Thursday the company is merging clinical drug trial work at its Bothell facility with operations at its company headquarters in Thousand Oaks, Calif.
She says laid-off employees can reapply for other positions within the company.
Xconomy, a business and technology news site that reported the job cuts, says the cutbacks leave about 70 employees in Bothell, and nearly 900 in Washington state. Pawlak confirms those figuresScar-Reducing Drug Shows Promise
Study links the Pill to increased lupus risk
It found women taking birth control pills, especially those who have just started taking them, may be 2 1/2 times more likely to contract the autoimmune disease.
The link between the two has been debated for some time. This new study in Arthritis Care and Research adds weight to earlier studies that have shown a connection.
Researchers speculate that estrogen from oral contraceptives could be responsible for the increased risk. Estrogen can affect the body's immune response which could then trigger a genetic predisposition to the disease. They add that the newer oral contraceptives are substantially less likely to increase the risk of lupus. But other experts say the risk is quite small.
Pharmaceuticals Provide a Takeover Tonic
FT.com
FDA Rebuffs Teva’s Citizen Petition on Generic Copaxone Filings
Generic Line
Supreme Court Asked to Review Prescriber Data Case
FDA Reverses Course, Drugmakers Allowed to Make Morphine Solution
Medtronic Wraps Up Buy of CoreValve
Panel Rejects Stryker OP-1 Bone Putty for PMA Approval
Minimally Invasive Technologies Expected to Be Boom Market
Crofelemer, First-in-Class Anti-Diarrheal Agent, Positive Clinical Results to be Discussed at 13th Annual US-Japan CMSP in Kolkata, India
Pradip K. Bardhan of the International Center for Diarrheal Disease Research (“ICDDR”) in Bangladesh will be summarizing the results from two clinical studies that evaluated the safety and efficacy of Napo’s novel anti-secretory anti-diarrheal agent, crofelemer (NP-303), in the treatment of adult acute infectious diarrhea (conducted in India by Glenmark) and cholera (conducted at the ICCDR in Bangladesh). The study of the effects of crofelemer in adult infectious diarrhea, predominantly from enterotoxigenic Escherichia coli (ETEC) infection, was conducted without the use of any antibiotics, while the study in adult patients suffering from cholera infection was conducted in combination with a single oral dose of azithromycin. These results collectively show that crofelemer represents a first-in-class treatment option as an antisecretory agent for the treatment of acute dehydrating watery diarrhea, with or without the use of antibiotics.
Perhaps the most important application of crofelemer is to address the devastating morbidity and mortality of ~2.5 million children under 5 who die each year primarily in developing countries, from the devastation of diarrhea and dehydration of cholera and watery diarrhea due to multiple etiologies and the global crisis in access to clean water. Cholera, for example, results in death for >50% of its victims without adequate rehydration. Current standard-of-care therapy focuses on rehydration therapy and antibiotic therapy to target the infectious agent. There are no current therapies for cholera which decrease the secretion of fluid into the small intestine. Patients are at maximum risk during the first 6-18 hours. Crofelemer demonstrated significant reduction (approximately 32%) in stool volume output in the first 6 hours, a trend which continued through the first 24 hours of observation — the period of time where patients are often in a life-threatening situation due to severe dehydration. In the severe acute watery diarrhea study, overall clinical success was achieved in about 75% of the crofelemer group, including statistically significant results on all seven measurements of diarrhea symptoms. Both these studies was conducted in adults.
A separate presentation will be given by Dr. Alan S. Verkman of the Departments of Medicine and Physiology at the University of California, San Francisco, California, discussing the mechanism of action of crofelemer as a first-in-class, small molecule dual inhibitor of CFTR chloride channel and calcium activated chloride channel (“CaCC”). Furthermore, this presentation will provide some of the preclinical results with other novel small molecule inhibitors of CFTR (“second gen CFTR”), which have been exclusively licensed by Napo from the University of California regents.
(See Abstracts below)
Lisa A. Conte, CEO of Napo Pharmaceuticals, Inc. commented: "Napo is thrilled that the important results of the trials of crofelemer for cholera and for severe adult acute infectious diarrhea are being presented in such a forum and I would like to thank Glenmark, Dr. Bardhan and the ICDDR for their contributions. We look forward to Glenmark’s anticipated introduction of crofelemer in India in 2010 and in other countries thereafter. Napo is committed to the development of crofelemer for pediatric populations and collaboration with both crofelemer and second gen CFTR to address the global impact of diarrhea diseases.”
Napo’s commercial licensee for crofelemer in the United States, Salix Pharmaceuticals, Inc., expects to file an NDA for the indication of chronic diarrhea in people living with HIV/AIDS in the first half of 2010. Crofelemer is in the final Phase 3 study for this indication and has been fast-tracked by the FDA.
J&J Cutting About 900 Jobs From Pharma Unit
NEW YORK-Diversified health care products company Johnson & Johnson said Thursday it will cut about 900 jobs, mainly from its Ortho-McNeil-Janssen Pharmaceuticals unit.
The cuts include a mix of attrition and hiring freezes. They are part of the company's strategy to trim its U.S. sales force and refocus its approach in the market, according to Kara Russell, spokeswoman for the Ortho-McNeil-Janssen Pharmaceuticals unit.
The cuts amount to about 6 percent of J&J's overall pharmaceutical sales force.
In January, the maker of baby shampoo, contraceptives and other health items forecast weaker results in 2009, blaming the global recession, unfavorable currency exchange rates and intensified pressure from both generic drugs and competitors' new products.
Pfizer's Oncology Business Unit Appoints Vice President of Medical Affairs
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“We are delighted that Dr. George – with her impressive record as a leader in global pharmaceutical organizations – will be joining Pfizer's Oncology Business Unit and look forward to her contributions in advancing science needed to bring innovative medicines to patients,” said Mace L. Rothenberg, M.D., senior vice president, Clinical Development and Medical Affairs for the Oncology Business Unit.
Dr. George possesses 20 years of experience in leading pharmaceutical organizations with expertise in medical affairs, clinical research and regulatory affairs. Most recently, she held the position of Senior Vice President of Drug Development and Chief Medical Officer atGPC Biotech, Inc. where she was responsible for the strategy and development activities for satraplatin and all early development compounds.
Her previous experience includes serving as Senior Vice President and Head of Oncology for Johnson & Johnson and as Vice President of Clinical Affairs at Ortho Biotech, Inc. Additionally, she has led the medical affairs group at Rhone-Poulenc Rorer (Sanofi-Aventis), worldwide clinical research and regulatory affairs at Gencell, and clinical research and development at Sandoz Pharmaceuticals Corporation (Novartis). Prior to joining industry she held an academic position at Institute Gustave Roussy, Villejuif, France for several years.
Dr. George received her M.Sc in Pharmacology from Montreal University in 1973, her M.D. from Paris University in 1975, and is board certified in Medical Oncology.
the Impact of the Withdrawal of Raptiva (efalizumab) on the Psoriasis Market
BioTrends will field its fourth annual TreatmentTrends(TM): Psoriasis survey on
A second report offered by BioTrends, ChartTrends(TM): Biologics in Psoriasis, is a report that is based on actual patient level audit data collected through a proprietary audit tool. In this report, 1000 patients who are currently being treated with biologic agents will be reviewed to analyze the treatment algorithm that culminates in the use of biologic agents, patient demographics/co-morbidities associated with specific biologic brand use, product switching incidence and rationale, and concomitant medications. A special section focused on switches from Raptiva will be included to understand if these patients migrate to other biologic brands or are discontinued altogether from biologic therapy. This report will be published in early June.
According to last year's TreatmentTrends(TM): Psoriasis report, market share for Raptiva had steadily declined since 2006 and only 44% of the dermatologists surveyed were using the product in their practices in
New drug shows promise in treating drug-resistant prostate cancer
A new therapy for metastatic prostate cancer has shown considerable promise in early clinical trials involving patients whose disease has become resistant to current drugs.
Chemists and biologists at UCLA and colleagues at several other institutions, including Memorial Sloan-Kettering Cancer Center, have created a new drug to treat a particularly lethal form of the disease, known as castration-resistant prostate cancer, or CRPC. Also referred to as hormone-refractory prostate cancer, CRPC is resistant to further treatment by anti-hormone drugs such as Casodex and Eulexin.
In an article published April 9 in the advanced online edition of the journal Science, the scientists describe the development and testing of two novel compounds, MDV3100 and RD162, which block the androgen receptor (AR) in CRPC cells, and report results from clinical trials in which MDV3100 was found to lower prostate-specific antigen (PSA) levels — a marker for tumor growth — in men with CRPC.
The new, small organic molecule MDV3100 was "designed as a very strong antagonist of the androgen receptor to stop the growth of any prostate cancer that requires the AR for propagation, which includes most forms of prostate cancer," said Michael Jung, UCLA professor of chemistry and biochemistry and a researcher at UCLA's Jonsson Comprehensive Cancer Center, whose research group synthesized both MDV3100 and RD162.
The biology research was carried out in the UCLA departments of medicine, urology and pharmacology by Charles Sawyers and his research group; Sawyers has since moved to Memorial Sloan-Kettering Cancer Center in New York, where he serves as chair of the human oncology and pathogenesis program. The UCLA patents for both compounds were licensed by the pharmaceutical company Medivation Inc., which chose to test MDV3100 in clinical trials.
The drug has successfully completed Phase 1 and Phase 2 clinical trials, and the Food and Drug Administration has agreed to allow Medivation to begin what Jung described as "the pivotal Phase 3 clinical trials."
The results of clinical studies with MDV3100 were described at the 2009 ASCO Genitourinary Cancer Symposium in February by the trials' principal investigator, Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center. In general, the drug, at 240 mg once a day, was very effective at lowering PSA levels and also in reducing the number of circulating tumor cells, without any significant toxicity.
"I think it is quite likely that the exciting results seen in the smaller population will also be evident in the larger Phase 3 trial and that the drug could be approved for use in the next few years," said Jung, who is also a member of the California NanoSystems Institute (CNSI) at UCLA.
Of 30 men with anti-androgen–resistant prostate cancer who received low doses of MDV3100 in the multisite Phase 1/2 trial designed to evaluate safety, 22 showed a sustained decline in PSA levels, an indication that their cancer was responding favorably to the drug. This trial is still underway, and results from a total of 140 patients receiving higher doses of the drug will be reported within the next year, Sawyer said.
The Phase 3 clinical trial will evaluate the drug's effect on survival in a large group of patients with metastatic prostate cancer.
MDV3100 and RD162 are second-generation anti-androgen therapies that prevent male hormones from stimulating the growth of prostate cancer cells. These new compounds appear to work well even in prostate cells that have a heightened sensitivity to hormones; that heightened sensitivity makes prostate cancer cells resistant to existing anti-androgen therapies.
Approximately 186,000 new cases of prostate cancer are diagnosed each year in the United States. The male hormones testosterone and dihydrotestosterone, which are also known as androgens, spur the growth of prostate cells, and drugs that block the receptors for these hormones are the most common treatment for the disease in its advanced, metastatic stage. Anti-androgen drugs, such as bicalutamide (Casodex), suppress the growth of cancer cells temporarily, but in most patients, the cancer ultimately develops resistance to drugs. Approximately 29,000 men in the United States die each year from the disease.
Prostate cancer becomes resistant to anti-androgen drugs when cancer cells begin to increase production of the androgen receptor, Sawyers said. When the level of androgen receptors on the cells' surface reaches a certain level, the drugs that originally suppressed the cancer actually begin to stimulate cancer growth.
Because of this backlash effect, many scientists have questioned whether blocking the androgen receptor is a wise course of action. Sawyers and his colleagues, however, believe that blocking the receptor is critical to successful treatment. They set out to design a new generation of drugs that can block the androgen receptor without unwanted side effects, even when levels of the receptor are high.
Researchers in Jung's and Sawyers' laboratories based their designs on a drug that tightly attaches to the site on the androgen receptor that binds with testosterone. If that site is blocked, the hormone cannot bind to prostate cells and tell the receptor to stimulate growth. Using this initial drug as a chemical scaffold, the researchers synthesized nearly 200 slightly different versions of the drug. They tested each one in the laboratory on prostate cancer cells that had been engineered to produce high levels of androgen receptor.
This screening yielded MDV3100 and RD162, molecules which tightly bind to the androgen receptor and do not show the cancer-stimulating effect of bicalutamide and other current anti-androgen drugs. The molecules were good candidates for drugs, because they are readily absorbed into the blood when taken orally and they persist in the bloodstream. The researchers tested the new drugs' effectiveness in mice with tumors derived from drug-resistant prostate cancer cells.
"To our delight, we found that these compounds caused very dramatic shrinkage of tumors in the mice," Sawyers said. "While treating these animals with bicalutamide produced a modest effect on their tumors, the new drugs caused the tumors to shrink dramatically, and in some animals almost completely."
Sawyers said the new drugs bind tightly enough to the natural hormone-binding site on androgen receptors to prevent most of them from functioning, even in cells with many androgen receptors.
The promising laboratory studies led Medivation to license the drugs for commercial development.
Medivation has received permission from the FDA for a large Phase 3 clinical trial of MDV3100 on about 1,200 patients with anti-androgen-resistant disease. This study will assess MDV3100's effect on cancer survival and will take several years.
While the preliminary results are promising, Sawyers said his laboratory will continue to seek further improvements in drug therapy for prostate cancer.
"There were some men in the initial trial in which the drug didn't work at all, and we want to find out why," he said. "It may be because the drug is not potent enough to overcome resistance due to androgen receptor over-expression. Or it may be that the cancers in these men are not driven by the androgen receptor anymore. Also, there were men who initially received benefit from the drug but then relapsed, and their PSA levels came back up. We want to understand the mechanism of that relapse and to try to develop drugs that prevent that renewed resistance."
For years, no treatment was available for CRPC; recently paclitaxel — a strongly cytotoxic drug — was approved.
'Unapproved' morphine to stay on market, FDA rules
WASHINGTON (CNN) -- A form of liquid morphine used by terminally ill patients will remain on the market even though it is an "unapproved drug," according to a decision by the Food and Drug Administration.
After talking with hospital and hospice organizations, which expressed concern that taking the product off the market would result in hardship for terminally ill patients and their caregivers, the agency decided to extend the usage of morphine sulfate oral solution 20 mg/ml.
The agency wants to ensure there is shortage of the drug while patients wait for an approved product to take its place.
"While the FDA remains committed to ultimately ensuring that all prescription drugs on the market are FDA approved, we have to balance that goal with flexibility and compassion for patients who have a few alternatives for the alleviation of their pain," Dr. Douglas Throckmorton, deputy director of the FDA's Center for drug Evaluation and Research, said Thursday.
"In light of the concerns raised by these patients and their health-care providers, we have adjusted our actions with regard to these particular products."
Last month, the FDA sent warning letters to nine companies telling them to stop manufacturing 14 unapproved narcotics that are widely used to treat pain.
Seven of those companies made or distributed the oral morphine.
The morphine elixir is widely used by terminal patients in hospital and home hospice care settings and is manufactured by Lehigh Valley Technologies Inc., Mallinckrodt Inc. Pharmaceuticals Group, Boehringer Ingelheim Roxane Inc. and Cody Laboratories, Inc.
In its warning letter last month, the agency gave the companies 60 days to stop manufacturing the drug before enforcement action was taken.
Thursday's announcement did not prompt immediate reactions from the companies. A spokesman for Cody Laboratories said the firm did not have all the details of the decision. Other companies did not immediately return calls from CNN.
The FDA estimates there are several thousand drugs, mostly older products, marketed illegally without FDA approval in this country. Once an illegally marketed drug is identified, enforcement action begins because the agency does not have information on the quality of these drugs and has not had an opportunity to approve their labeling. In 1976 the agency began a program to bring companies manufacturing these drugs into compliance.
Thursday's announcement applies only to the morphine sulfate elixir 20mg/ml, and the warning letters sent to the other product manufacturers are still in effect.
Currently there are no approved morphine sulfate oral solution 20mg/ml products on the market. Until there are, the FDA says it will allow companies making and distributing the unapproved drugs to continue, until 180 days after any company receives approval to manufacture a new morphine replacement drug of the same dosage.
The FDA says it expects all companies marketing unapproved drugs to submit the necessary applications to get approval for those drugsTest quickly assesses whether Alzheimer's drugs are hitting their target
A test developed by physician-scientists at Washington University School of Medicine in St. Louis may help assess more quickly the ability of Alzheimer's drugs to affect one of the possible underlying causes of Alzheimer's disease in humans, accelerating the development of new treatments.
Scientists used the test to show that an Alzheimer's drug given to healthy volunteers reduced production of a substance known as amyloid beta (A-beta), a normal byproduct of human metabolism that builds to unhealthy levels forming brain plaques in Alzheimer's patients. The drug candidate, LY450139, which is also known as semagacestat, is being studied in clinical trials by Eli Lilly and Company.
Ongoing clinical trials are studying the effect that semagacestat may have on cognitive function and biochemical and brain imaging biomarkers in patients with Alzheimer's disease. Washington University researchers wanted to see whether the new measurement technique, stable isotope-linked kinetics (SILK), could detect the study drug's impact on A-beta synthesis in healthy volunteers.
"Bringing an Alzheimer's disease drug into clinical trials from tests in animal models has always been challenging," says study director Randall Bateman, M.D., a Washington University neurologist who treats patients at Barnes-Jewish Hospital. "We haven't had a way to quickly and accurately assess a drug's effects, and that meant there always had to be some degree of educated guesswork when it came to setting the optimal dosage for humans. SILK may help to eliminate much of that guesswork."
The results appear online in Annals of Neurology on April 10.
Scientists are unsure whether increased A-beta production, reduced clearance or a combination of the two lead to the A-beta buildup in the brain, a process that many believe triggers Alzheimer's disease. Bateman and his colleagues are currently using SILK to try to answer this question.
Until SILK, there has not been a way to directly measure the production or clearance of A-beta. The efficacy of potential new Alzheimer's drug candidates has been assessed by monitoring the cognitive functions of patients with the disease for extended periods of time, which require large, lengthy and expensive studies.
In their double-blind study, scientists gave 20 healthy volunteers varying doses of either a study drug or a placebo. At the start of the SILK test, volunteers were connected to an intravenous drip that gave them a slightly altered form of the amino acid leucine, which is a component of A-beta.
Over the course of several hours, cells in the brain picked up the labeled leucine and incorporated it into the new copies made of A-beta and other proteins. The scientists took periodic samples of the subjects' cerebrospinal fluid to determine how much of the A-beta included altered leucine.
Tracking the rise of the percentage of labeled A-beta over time reveals the A-beta production rate. Scientists then stop the leucine labeling but continue analyzing spinal fluid samples. As the body removed old A-beta and made new A-beta, the percentage of A-beta containing altered leucine dropped, revealing the A-beta clearance rate.
The results suggest a dose-dependent drop in A-beta production, with an 84 percent reduction in A-beta production being measured with the highest study drug dose.
The SILK procedure takes 36 hours, but provides scientists a more detailed assessment of amyloid beta production and clearance levels than they can obtain through conventional methods.
"You could use a spinal tap to look directly at the amount of A-beta present in the cerebrospinal fluid, but we've shown that natural processes cause A-beta levels to change dynamically," says Bateman. "Such changes make it more difficult to assess the effects of a drug in that fashion."
Thursday, April 9, 2009
FDA Advisory Committee Recommendation on Seroquel XR Supplemental New Drug Applications
WILMINGTON, Del., April 08, 2009 /PRNewswire-FirstCall/ -- Today, the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) conducted a review of the safety and efficacy of supplemental new drug applications (sNDA) for SEROQUEL XR (quetiapine fumarate) extended-release tablets proposed for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).
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The Advisory Committee concluded:
Howard Hutchinson, M.D., Chief Medical Officer of AstraZeneca, said: "We are pleased that the committee found SEROQUEL XR to be effective and acceptably safe for use as adjunctive therapy for the treatment of MDD. Although the committee recognized the effectiveness of SEROQUEL XR as monotherapy for MDD and GAD, they had concerns around the long-term safety profile in these new populations. We look forward to having further discussions with the FDA regarding both sNDAs."
The FDA frequently convenes advisory committee meetings to obtain independent expert guidance and recommendations on clinical matters. While the FDA is not required to follow this guidance, the agency usually takes the advice into consideration when rendering its final decisions on pending applications and other public health matters.
SEROQUEL XR is not approved for the treatment of MDD and GAD.
SEROQUEL XR, a once-daily, extended-release tablet formulation of SEROQUEL(R) (quetiapine fumarate) tablets, was approved in the U.S. in 2007 for the acute and maintenance treatment of schizophrenia in adult patients and in October 2008 for the acute treatment of the depressive episodes associated with bipolar disorder, the manic and mixed episodes associated with bipolar I disorder, and the maintenance treatment of bipolar I disorder as adjunctive therapy to lithium or divalproex.
SEROQUEL XR is indicated for the treatment of acute depressive episodes associated with bipolar disorder, acute manic or mixed episodes associated with bipolar I disorder as monotherapy and as an adjunct to lithium or divalproex; maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex, and acute and maintenance treatment of schizophrenia. SEROQUEL is indicated for the treatment of depressive episodes in bipolar disorder; acute manic episodes in bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex; maintenance treatment of bipolar I disorder as adjunct therapy to lithium or divalproex; and schizophrenia. Patients should be periodically reassessed to determine the need for continued treatment and the appropriate dose.
Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics. Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.
In long-term clinical trials of quetiapine, hyperglycemia (fasting glucose Greater Than or Equal To 126 mg/dL) was observed in 10.7% of patients receiving quetiapine (mean exposure 213 days) vs. 4.6% in patients receiving placebo (mean exposure 152 days).
Clinically significant increases in cholesterol (7%-16% for quetiapine vs. 3%-9% for placebo) and triglycerides (8%-23% for quetiapine vs. 5%-16% for placebo) have been observed in clinical trials.
The proportion of patients in clinical trials meeting a weight gain criterion of Greater Than or Equal To 7% of body weight was 5%-23% for quetiapine vs. 0%-7% for placebo.
A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include immediate discontinuation of antipsychotic drugs.
Leukopenia, neutropenia, and agranulocytosis (including fatal cases), have been reported temporally related to atypical antipsychotics, including quetiapine. Patients with a pre-existing low white blood cell (WBC) count or a history of drug induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy. In these patients, SEROQUEL XR and SEROQUEL should be discontinued at the first sign of a decline in WBC absent other causative factors. Patients with neutropenia should be carefully monitored, and SEROQUEL XR and SEROQUEL should be discontinued in any patient if the absolute neutrophil count is <>
Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of TD.
Warnings and Precautions also include the risk of orthostatic hypotension, cataracts, seizures, hyperprolactinemia, and possibility of suicide attempts. Examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment. The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high risk patients should accompany drug therapy.
The most commonly reported adverse reactions associated with the use of SEROQUEL vs. placebo in clinical trials for schizophrenia and bipolar disorder were somnolence (18%-57% vs. 8%-15%), dry mouth (9%-44% vs. 3%-13%), dizziness (9%-18% vs. 5%-7%), constipation (8%-10% vs. 3%-5%), asthenia (5%-10% vs. 3%-4%), abdominal pain (4%-7% vs. 1%-3%), postural hypotension (4%-7% vs. 1%-2%), pharyngitis (4%-6% vs. 3%), weight gain (5%-6% vs. 1%-3%), lethargy (5% vs. 2%), nasal congestion (5% vs. 3%), SGPT increased (5% vs. 1%), and dyspepsia (5%-7% vs. 1%-4%).
Merck & Co., Inc. and Cardiome Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation
"This agreement underscores Merck's ongoing commitment to the research and development of new cardiovascular drugs," said Luciano Rossetti M.D., senior vice president and franchise head, Atherosclerosis and Cardiovascular, Merck Research Laboratories. "Vernakalant is an important addition to our broad portfolio of products and candidates that target multiple aspects of heart disease."
“Given Merck's long-established leadership in the cardiovascular space, we believe there is no company better suited to advance vernakalant,” said Bob Rieder, chairman and chief executive officer of Cardiome. “This collaboration places Cardiome in a strong financial position as we conclude our strategic review, and moves the Company closer to providing doctors with an important tool to address this critical unmet medical need.”
Under terms of the agreement, Merck will pay Cardiome an initial fee of US$60 million. In addition, Cardiome is eligible to receive up to US$200 million in payments based on achievement of certain milestones associated with the development and approval of vernakalant products (including a total of US$35 million for initiation of a planned Phase III program for vernakalant [oral] and submission for regulatory approval in Europe of vernakalant [IV]), and up to US$100 million for milestones associated with approvals in other subsequent indications of both the intravenous and oral formulations. Also, Cardiome will receive tiered royalty payments on sales of any approved products and has the potential to receive up to US$340 million in milestone payments based on achievement of significant sales thresholds.
Cardiome has retained an option to co-promote vernakalant (oral) with Merck through a hospital-based sales force in the United States. Merck will be responsible for all future costs associated with the development, manufacturing and commercialization of these candidates. Merck has granted Cardiome a secured, interest-bearing credit facility of up to US$100 million that Cardiome may access in tranches over several years commencing in 2010.
Vernakalant (IV) is an investigational candidate being evaluated for its ability to terminate an atrial fibrillation episode and return the heart to normal rhythm. Cardiome's co-development partner in North America, Astellas Pharma U.S., Inc., submitted a New Drug Application with the U.S. Food and Drug Administration (FDA) for KYNAPID™ (vernakalant hydrochloride) Injection in December 2006 that included results from two pivotal Phase III clinical trials. In December 2007, the Cardiovascular and Renal Drugs Advisory Committee recommended that the FDA approve vernakalant (IV) for rapid conversion of atrial fibrillation. In August 2008, the FDA issued an Approvable action letter requesting additional information.
Vernakalant (oral) is being evaluated as an oral maintenance therapy for the long-term prevention of atrial fibrillation recurrence. A Phase IIb double-blind, placebo-controlled, randomized, dose-ranging clinical trial in patients at risk of recurrent atrial fibrillation showed that at the 500 mg dose, vernakalant (oral) significantly reduced the rate of atrial fibrillation relapse as compared to placebo.
The effectiveness of the collaboration agreement is subject to the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, if applicable, as well as other customary closing conditions. The agreement between Cardiome and Astellas Pharma U.S., Inc. for vernakalant (IV) in the United States, Canada and Mexico is unaffected by this agreement.
Research could lead to new non-antibiotic drugs to counter hospital infections
Lack of an adequate amount of the mineral phosphate can turn a common bacterium into a killer, according to research to be published in the April 14, 2009, issue of the Proceedings of the National Academies of Science. The findings could lead to new drugs that would disarm the increasingly antibiotic-resistant pathogen rather than attempting to kill it.
Pseudomonas aeruginosa is one of the most serious hospital-acquired pathogens. A common cause of lung infections, it is also found in the intestinal tract of 20 percent of all Americans and 50 percent of hospitalized patients in the United States.
It is one of the hundreds of bacteria that colonize the human intestinal tract, usually causing no apparent harm. It might even be beneficial to its host. Once the host is weakened by an illness, surgical procedure or immunosuppressive drugs, however, P. aeruginosa can cause infection, inflammation, sepsis and death.
Why P. aeruginosa can suddenly turn on its host has eluded researchers—until now. Scientists have long known that after an operation or organ surgery, levels of inorganic phosphate fall. The authors of the PNAS paper, led by scientists at the University of Chicago, hypothesized that phosphate depletion in the stressed intestinal tract signals P. aeruginosa to become lethal.
To test this theory, they let worms (Caenorhabditis elegans) feed on "lawns" of P. aeruginosa and Escherichia coli grown in both low-phosphate and high-phosphate media. Only the worms that ate P. aeruginosa with low levels of phosphate died. The researchers dubbed the phenomenon "Red Death" since unexpected large red spots appeared on the worms before they died.
"These findings provide novel insight into the mechanisms by which P. aeruginosa is able to shift from indolent colonizer to a lethal pathogen when present in the intestinal tract of a stressed host," said Alexander Zaborin, lead author of the study and a research professional at the University of Chicago’s Department of Surgery.
"It's almost as if the bacterium sense when to strike," said John Alverdy, corresponding author of the study and professor of surgery at the University of Chicago Medical Center. "That should come as no surprise since the bacteria are smart, having been around for 2 billion years."
Bacteria seek phosphate as an important nutrient, Alverdy explained. And rather than try to look for it in the blood steam of critically ill patients, where they would encounter armies of antibiotics and disease-fighting white blood cells, they find it inside organ tissues. This process damages and sometimes even kills their host.
Experiments with mice showed that the harm caused when P. aeruginosa becomes activated to express lethal toxins inside the intestinal tract can be mitigated by providing excess phosphate.
The research findings could lead to a pharmaceutical product that would restore healthy phosphate levels in the intestines of such stressed and compromised patients, Alverdy said.
"Antibiotics attempt to kill harmful bacteria, but in the process they often kill beneficial bacteria," said Olga Zaborina, an associate professor at the University of Chicago’s Department of Surgery and another key researcher in this study. "A more sensible approach to fighting infectious diseases may be to try to understand the circumstances that provoke a microbe to cause harm in the first place and then find ways to pacify them without destroying them."
Containment on a case-by-case basis might be a more effective and longer-lasting strategy than a scorched earth policy, Alverdy said. Midway Pharmaceuticals, which Alverdy founded in 2005, is developing a pipeline of non-antibiotic compounds that contain or disarm specific bacteria.
Appreciation of the subtle mechanisms in pathogens that colonize the intestinal tract of critically ill patients has important implications for the design of phosphate-based compounds that might prevent P. aeruginosa and other pathogens from turning lethal, the researchers concluded.
Despite the use of powerful antibiotics, P. aeruginosa remains a leading cause of sickness and death among hospitalized patients who have undergone surgery or have reduced immunity. If the bacterium attacks critical body organs such as the lungs, urinary tract and kidneys, it is likely to be fatal. P. aeruginosa thrives on moist surfaces, so it is often found on catheters, causing cross-hospital infections. It is also implicated in a common form of dermatitis associated with poor hygiene and inadequate maintenance of hot tubs.
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Drug shows activity in men with advanced prostate cancer
A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published today in Science Express, the online version of the journal Science.
Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.
The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.
Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.
"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.
Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.
Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.
"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers. Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.
According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing. They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.
The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium. The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009 (see abstract: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=64&abstractID=20500).
"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.
Stem cell therapy makes cloudy corneas clear, according to Pitt researchers
PITTSBURGH, April 9 – Stem cells collected from human corneas restore transparency and don't trigger a rejection response when injected into eyes that are scarred and hazy, according to experiments conducted in mice by researchers at the University of Pittsburgh School of Medicine. Their study will be published in the journal Stem Cells and appears online today.
The findings suggest that cell-based therapies might be an effective way to treat human corneal blindness and vision impairment due to the scarring that occurs after infection, trauma and other common eye problems, said senior investigator James L. Funderburgh, Ph.D., associate professor, Department of Ophthalmology. The Pitt corneal stem cells were able to remodel scar-like tissue back to normal.
"Our experiments indicate that after stem cell treatment, mouse eyes that initially had corneal defects looked no different than mouse eyes that had never been damaged," Dr. Funderburgh said.
The ability to grow millions of the cells in the lab could make it possible to create an off-the-shelf product, which would be especially useful in countries that have limited medical and surgical resources but a great burden of eye disease due to infections and trauma.
"Corneal scars are permanent, so the best available solution is corneal transplant," Dr. Funderburgh said. "Transplants have a high success rate, but they don't last forever. The current popularity of LASIK corrective eye surgery is expected to substantially reduce the availability of donor tissue because the procedure alters the cornea in a way that makes it unsuitable for transplantation."
A few years ago, Dr. Funderburgh and other University of Pittsburgh researchers identified stem cells in a layer of the cornea called the stroma, and they recently showed that even after many rounds of expansion in the lab, these cells continued to produce the biochemical components, or matrix, of the cornea. One such protein is called lumican, which plays a critical role in giving the cornea the correct structure to make it transparent.
Mice that lack the ability to produce lumican develop opaque areas of their corneas comparable to the scar tissue that human eyes form in response to trauma and inflammation, Dr. Funderburgh said. But three months after the lumican-deficient mouse eyes were injected with human adult corneal stem cells, transparency was restored.
The cornea and its stromal stem cells themselves appear to be "immune privileged," meaning they don't trigger a significant immune response even when transplanted across species, as in the Pitt experiments.
"Several kinds of experiments indicated that the human cells were alive and making lumican, and that the tissue had rebuilt properly," Dr. Funderburgh noted.
In the next steps, the researchers intend to use the stem cells to treat lab animals that have corneal scars to see if they, too, can be repaired with stem cells. Under the auspices of UPMC Eye Center's recently established Center for Vision Restoration, they plan also to develop the necessary protocols to enable clinical testing of the cells.
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Rheumatoid Arthritis Therapeutics in China
In 2007, the prevalence of rheumatoid arthritis (RA) in
State health insurance funds the treatment cost for NSAIDs and some DMARDs such as Methotrexate (MTX). However, a majority of the population has no health insurance, putting pressure on out-of-pocket payment, or go without treatment.
Frost & Sullivan, Research Analyst
"Recent work productivity studies have confirmed that better disease awareness and availability of treatment options have resulted in fewer patients ceasing to work and more patients reporting lower impact of their disease on work as well as family and social activities," she further elaborates.
Methotrexate (MTX), a DMARD (disease-modifying anti-rheumatic drug) has been traditionally used to treat RA. It is also the most used form of treatment in rheumatoid arthritis, especially with generic forms available. Currently, combination therapies between DMARDs and NSAIDs (non-steroidal anti-inflammatory drugs) are commonly practiced.
DMARDs capture the majority of the RA therapeutics market owing to the availability of reimbursement for treatment with these drugs and their easy availability over the counter. DMARDs are expected to retain majority share in the forecast period as well.
According to Rajan, "Biologics are used in combination with DMARDs for moderate to severe RA patients. Some biologic drugs are currently reimbursed, if treated in government hospitals. Physicians opine that with more drugs brought into the hospital formularies, the usage of biologics would increase for treatment earlier in the disease."
Though there are new drugs available for treating RA, specialists in china are likely to continue using DMARDs as their first line therapy, as they have the most experience with this drug class, and it is seen as the most cost effective treatment option. Even though biologics are highly effective and recommended for treatment, they are likely to be the third line of treatment, due to their high cost. Physicians are willing to use biologics if they are listed in the hospital formulary and if they are affordable to their patients (current price range is seen to be out of reach of most patients). Physicians are of the opinion that more studies are required to make them feel confident in using biologics, but the cost of treatment is likely to restrain the high use of the drug class.
Wednesday, April 8, 2009
American College of Pediatricians: Another Blow to Children's Rights
Children's rights have suffered a severe blow in the last week.
During the last two decades, medical research has even confirmed the existence of genetically-determined gender differences in brain anatomy, neural pathways, cognitive processing, and hormone physiology. These account for differences in how men and women relate to people and the world around them, which in turn explains why parenting differences between the genders are not mere social constructs. Mothers and fathers are not interchangeable and neither is dispensable. Two women cannot compensate for the absence of a father, and two men cannot fill the unique role of a mother. In addition, social science research clearly demonstrates that the further society deviates from the model of the fundamental mother/father family unit, the more children and society suffer.
The American College of Pediatricians asks, in hope and challenge, when will legislatures and the courts place the real needs of children ahead of or at least on an equal plane with the wants of adults?
FDA Approves Label Change for Non-Invasive Fibroid Treatment
TIRAT CARMEL,
"In allowing doctors to destroy the entire fibroid, we believe the FDA has demonstrated further confidence in the safety and efficacy of the non-invasive ExAblate system," said
The FDA label change was based on a growing body of evidence supporting the system's safety and efficacy, including the results of a study published in the
"We're extremely pleased that the FDA approved this important label change and believe this underscores the safety of our system, the only non-invasive treatment for uterine fibroids available today," said Dr.
"Evidence supports removing fibroids that distort the uterine cavity to increase pregnancy rates and decrease the rates of miscarriage," Dr. Brown added. This trial tests the premise in women who have not been eligible for minimally invasive treatment.
The Fertility Enhancement study is being conducted at the Mayo Clinic in
To date, InSightec has reported 54 pregnancies, 22 deliveries with 11 ongoing pregnancies with women who previously underwent the ExAblate procedure.
Core Essence Receives FDA Approval for SECURUS(TM), an Innovative Knotless Suture Anchor System
"SECURUS is a game-changing product in the area of rotator cuff repair," said
SECURUS is specifically designed to give surgeons the motivation to make the transition to minimally invasive surgery at the precise time when the demand for arthroscopic surgery is more significant than ever. The 510(k) regulatory approval means Core Essence will be on track to ramp up distribution over the course of 2009.
SECURUS is an innovative implantable platform system that locks down sutures in arthroscopic tendon repair surgeries, particularly high volume shoulder procedures focusing on rotator cuff repair. The product is available in 5.5mm and 7.0mm diameters to address varying degrees of bone quality, as well as rescue potential. In addition, the SECURUS system presents a number of distinct advantages to alternatives currently available on the market, including: consistent, reproducible bone and suture retention strength, tactile tensioning of sutures (allowing the surgeon to 'feel' the tension in the soft tissue prior to locking the anchor), and a readily revisable implant system. Unlike most current knotless anchors, SECURUS can be adjusted intraoperatively and even removed and replaced.
Dr.
In addition to SECURUS, Core Essence has recently launched novel orthopedic product platforms including Seg-Way(TM), a synchronized endoscopic guide system for carpel tunnel syndrome; reNOVO(TM), a suture anchor system, and reVERTO(TM), a shape memory staple system indicated for arthrodesis and skeletal fixation procedures.
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