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Post by GodFather on Oct 21, 2013 19:31:33 GMT 5.5
Potential new drug for some patients with treatment-resistant lung cancer
The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
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Post by GodFather on Oct 21, 2013 19:33:14 GMT 5.5
GSK and Genmab announce submission to US regulatory authorities for Arzerra® (ofatumumab)
GlaxoSmithKline plc (LSE/NYSE: GSK) and Genmab A/S (OMX: GEN) have announced the submission of a supplemental Biologics License Application (sBLA) to the US Food and Drug Administration (FDA) for the use of Arzerra® (ofatumumab) in combination with an alkylator-based therapy, to be used for treatment of CLL patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.
The application is based primarily on results from an international, multi-centre, randomised Phase III study of ofatumumab in combination with chlorambucil versus chlorambucil alone in more than 400 patients with previously untreated CLL. Headline results from this trial were announced in May, 2013 and the full study results are scheduled to be presented at the 2013 American Society of Hematology Annual Meeting in December.
About Chronic Lymphocytic Leukaemia
CLL is the most common form of leukaemia in adults. Based on estimates by the American Cancer Society, CLL will account for more than 15,680 new cases and more than 4,580 deaths in the United States of America alone in 2013. At present, no curative chemotherapy is available.
About Arzerra® (ofatumumab)
Ofatumumab is not approved or licensed anywhere in the world for use in patients who have not received treatment for CLL. Ofatumumab is a human monoclonal antibody which targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops2. Ofatumumab is being developed under a co-development and collaboration agreement between Genmab and GlaxoSmithKline.
GSK - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.
Genmab is a publicly traded, international biotechnology company specializing in the creation and development of differentiated human antibody therapeutics for the treatment of cancer. Founded in 1999, the company's first marketed antibody, ofatumumab (Arzerra®), was approved to treat chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab after less than eight years in development. Genmab's validated and next generation antibody technologies are expected to provide a steady stream of future product candidates. Partnering of innovative product candidates and technologies is a key focus of Genmab's strategy and the company has alliances with top tier pharmaceutical and biotechnology companies.
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Post by GodFather on Oct 28, 2013 7:54:12 GMT 5.5
International collaboration finds 11 new Alzheimer's genes to target for drug discovery
University of Miami Miller School of Medicine researchers played a key role in the largest international Alzheimer's disease genetics collaboration to date, which identified 11 new regions of the genome that contribute to late-onset Alzheimer's disease, doubling the number of potential genetics-based therapeutic targets to investigate. Published October 27 in Nature Genetics, the study gives a broader view of the genetic factors contributing to Alzheimer's and expands the understanding of the disease to new areas, including the immune system, where a genetic overlap with other neurodegenerative diseases, including multiple sclerosis and Parkinson's disease, was identified.
In 2011, the world's four largest research consortia on the genetics of Alzheimer's disease joined efforts to discover and map the genes that contribute to Alzheimer's, forming the International Genomics of Alzheimer's Project (IGAP). The team collected genetic information from 25,500 Alzheimer's disease patients and 49,038 controls from 15 countries to perform this two-stage meta-analysis that resulted in the discovery of 11 new genes in addition to those already known, and the identification of 13 other genes, yet to be validated.
Margaret A. Pericak-Vance, Ph.D., the Dr. John T. Macdonald Foundation Professor of Human Genomics and Director of the John P. Hussman Institute for Human Genomics at the Miller School, and Lindsay A. Farrer, Ph.D., from Boston University, led the analysis teams for the American Alzheimer's Disease Genetics Consortium, which includes nearly all of the nation's researchers working on the genetics of Alzheimer's, as well as many investigators and resources of the 29 federally funded Alzheimer's Disease Centers.
Several of the genes the researchers identified confirmed known biological pathways of Alzheimer's disease, including the role of the amyloid (SORL1, CASS4) and tau (CASS4, FERMT2) pathways. Newly discovered genes involved in the immune response and inflammation (HLA-DRB5/DRB1, INPP5D, MEF2C) reinforced a pathway implied by previous work (on CR1, TREM2). Additional genes related to cell migration (PTK2B), lipid transport and endocytosis (SORL1) also were confirmed, and new hypotheses emerged related to hippocampal synaptic function (MEF2C, PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4), as well as myeloid and microglial cell functions (INPP5D).
One of the more significant new associations was found in the HLA-DRB5/DRB1 region, one of the most complex parts of the genome, which plays a role in the immune system and inflammatory response. It also has been associated with multiple sclerosis and Parkinson's disease, suggesting that the diseases where abnormal proteins accumulate in the brain may have a common mechanism involved, and possibly a common drug target.
"The discovery of novel pathways is very encouraging considering the limited success of Alzheimer's disease drugs tested so far," Pericak-Vance said. "Our findings bring us closer toward identifying new drug targets for Alzheimer's and other neurodegenerative diseases. We'll continue to expand and analyze our data set with this incredible group so that we can better understand the genetic influences on this devastating disease, and find new medical and therapeutic interventions."
Other Miller School co-authors include the Hussman Institute's Gary Beecham, Ph.D., assistant professor of human genetics; Eden R. Martin, Ph.D., professor of human genetics; John R. Gilbert, Ph.D., professor of human genetics; Kara Hamilton-Nelson, M.S., project manager for research support; and Brian Kunkle, Ph.D., postdoctoral associate; and Amanda Meyers, Ph.D., associate professor of psychiatry and behavioral sciences.
The IGAP includes contributions from the Alzheimer's Disease Genetics Consortium (ADGC) in the United States, which is led by Gerard Schellenberg, Ph.D., Perelman School of Medicine at the University of Pennsylvania; the European Alzheimer's Disease Initiative in France, led by Philippe Amouyel, M.D., Ph.D., at the Institute Pasteur de Lille and Lille University; the Genetic and Environmental Risk in Alzheimer's Disease from the United Kingdom, led by Julie Williams, Ph.D., at Cardiff University; the neurology subgroup of the Cohorts for Heart and Aging in Genomic Epidemiology, led by Sudha Seshadri, M.D., at Boston University School of Medicine; as well as teams from the University of Miami, Vanderbilt University, and Columbia University in the United States, among others.
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Post by GodFather on Oct 29, 2013 11:16:21 GMT 5.5
Excess omega-3 fatty acids could lead to negative health effects
A new review suggests that omega-3 fatty acids taken in excess could have unintended health consequences in certain situations, and that dietary standards based on the best available evidence need to be established. "What looked like a slam dunk a few years ago may not be as clear cut as we thought," said Norman Hord, associate professor in OSU's College of Public Health and Human Sciences and a coauthor on the paper.
"We are seeing the potential for negative effects at really high levels of omega-3 fatty acid consumption. Because we lack valid biomarkers for exposure and knowledge of who might be at risk if consuming excessive amounts, it isn’t possible to determine an upper limit at this time."
Previous research led by Michigan State University's Jenifer Fenton and her collaborators found that feeding mice large amounts of dietary omega-3 fatty acids led to increased risk of colitis and immune alteration. Those results were published in Cancer Research in 2010.
As a follow-up, in the current issue of the journal Prostaglandins, Leukotrienes & Essential Fatty Acids, Fenton and her co-authors, including Hord, reviewed the literature and discuss the potential adverse health outcomes that could result from excess consumption of omega-3 fatty acids.
Studies have shown that omega-3s, also known as long chain polyunsaturated fatty acids (LCPUFAs), are associated with lower risk of sudden cardiac death and other cardiovascular disease outcomes.
"We were inspired to review the literature based on our findings after recent publications showed increased risk of advanced prostate cancer and atrial fibrillation in those with high blood levels of LCPUFAs," Fenton said.
Omega-3 fatty acids have anti-inflammatory properties, which is one of the reasons they can be beneficial to heart health and inflammatory issues. However, the researchers said excess amounts of omega-3 fatty acids can alter immune function sometimes in ways that may lead to a dysfunctional immune response to a viral or bacterial infection.
"The dysfunctional immune response to excessive omega-3 fatty acid consumption can affect the body's ability to fight microbial pathogens, like bacteria," Hord said.
Generally, the researchers point out that the amounts of fish oil used in most studies are typically above what one could consume from foods or usual dosage of a dietary supplement. However, an increasing amount of products, such as eggs, bread, butters, oils and orange juice, are being "fortified" with omega-3s. Hord said this fortified food, coupled with fish oil supplement use, increases the potential for consuming these high levels.
"Overall, we support the dietary recommendations from the American Heart Association to eat fish, particularly fatty fish like salmon, mackerel, lake trout or sardines, at least two times a week, and for those at risk of coronary artery disease to talk to their doctor about supplements," he said.
"Our main concern here is the hyper-supplemented individual, who may be taking high-dose omega-3 supplements and eating four to five omega-3-enriched foods per day," Hord added. "This could potentially get someone to an excessive amount. As our paper indicates, there may be subgroups of those who may be at risk from consuming excess amounts of these fatty acids."
Hord said there are no evidence-based standards for omega-3 intake and no way to tell who might be at health risk if they consume too high a level of these fatty acids.
"We're not against using fish oil supplements appropriately, but there is a potential for risk," Hord said. "As is all true with any nutrient, taking too much can have negative effects. We need to establish clear biomarkers through clinical trials. This is necessary in order for us to know who is eating adequate amounts of these nutrients and who may be deficient or eating too much.
"Until we establish valid biomarkers of omega-3 exposure, making good evidence-based dietary recommendations across potential dietary exposure ranges will not be possible."
Sanjoy Ghosh from University of BC-Okanagan, Canada and Eric Gurzell from Michigan State University also contributed to this study, which was supported by grants from the National Institutes of Health and the Canadian Diabetes Association.
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Post by GodFather on Oct 29, 2013 11:17:38 GMT 5.5
Global Lung Cancer Coalition to identify patient challenges and improve support strategies in partnership with Boehringer IngelheimThe Global Lung Cancer Coalition (GLCC) announced today, at the 15th World Conference on Lung Cancer (WCLC) in Sydney, Australia, a campaign, supported by Boehringer Ingelheim (BI), to increase the knowledge and understanding of real world challenges facing individuals and families battling lung cancer. 'Lung Cancer: We're Listening' will gather much needed feedback from individuals touched by lung cancer - including patients, carers, family members, friends, healthcare professionals and work colleagues.
"By gathering insights and listening to real-life experiences from those directly affected by lung cancer, we can increase our knowledge and understanding of the challenges faced by lung cancer patients," said Dr Matthew Peters, chair of The Global Lung Cancer Coalition. "This knowledge can be used by the GLCC and shared with appropriate healthcare providers to effect change and improve patient-centric programmes, services and tools. This closely aligns with the GLCC's commitment to improving outcomes for all lung cancer patients and placing lung cancer squarely on the global health agenda."
Lung cancer is not only the most common cancer in the world, accounting for 1.6 million new cancer cases each year,1 but it is also the biggest cancer killer.2 Lung cancer is not just one disease; there are distinct subtypes and tailored approaches to treatment can improve patient outcomes. However, there is still a lack of understanding of the disease, and its impact on patients and those caring for them. A key driver of 'Lung Cancer: We're Listening' is a global need to better understand the real world challenges of lung cancer patients. By learning more about their specific challenges with many topics, including relating to changes in roles and relationships, stigmatisation, and difficulty communicating with their healthcare team, the campaign will help to improve the support and information available to them.
'Lung Cancer: We're Listening' adopts a unique approach to gathering patient feedback by minimizing the text-based feedback format and focusing on presenting the survey visually. A novel online tool, with a simple navigation, asks respondents to click on predefined graphics, symbols and elements within a web-based visual world to give their feedback on issues that are relevant to them. The visual elements represent challenges and issues of importance in the lives of lung cancer patients and their caregivers and families. The graphics and symbols they select will reveal their most pressing issues and concerns, mirroring over time the lung cancer patient's real world agenda and experiences.
This approach is the first of its kind designed to 'listen in' on the real world of lung cancer patients, and bridge the gap between healthcare providers and their patients' situations. Results will be shared with the lung cancer community and the insights shared with those involved in providing patient services to aid the development of new programmes, services and educational materials that better meet patients' needs.
"We need to understand how patients feel, in order to better help them," said Prof Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "With patients at the centre of our commitment to oncology, together with the GLCC we can use 'Lung Cancer: We're Listening' to inform programmes on a global scale and to develop more effective approaches to support the lung cancer community by improving patients’ lives beyond treatment."
The 'Lung Cancer: We're Listening' website will launch in mid-November to coincide with Lung Cancer Awareness Month.
About Lung Cancer
Lung cancer is the biggest cancer killer in the world with incidence rates higher in men than in women, it accounts for 1.6 million new cancer cases annually. Because of its poor prognosis, 1.38 million deaths each year are attributable to lung cancer. Overall, lung cancer is the cause of 18% of all cancer deaths and approximately 13% of all new cases of cancer are lung cancers.(1,3)
About the Global Lung Cancer Coalition (GLCC)
Established in 2001, the GLCC comprises 28 non-government patient organisations from Argentina, Australia, Bulgaria, Canada, Denmark, France, Germany, Ireland, Italy, Japan, Netherlands, Norway, Slovenia, Spain, Sweden, Switzerland, UK and US.
The GLCC is committed to improving disease outcomes for all lung cancer patients and aims to address the following issues:
place lung cancer on the global healthcare agenda
change public perceptions and lessen the stigma of lung cancer
empower lung cancer patients to take an active role in their care
effect change in legislative or regulatory policies to optimise treatment and care
About Boehringer Ingelheim in Oncology
Building on scientific expertise and excellence in the fields of pulmonary and cardiovascular medicine, metabolic disease, neurology, virology and immunology, Boehringer Ingelheim has embarked on a major research programme to develop innovative cancer drugs. Working in close collaboration with the international scientific community and a number of the world’s leading cancer centres, Boehringer Ingelheim' s commitment to oncology is underpinned by using advances in science to develop a range of targeted therapies for various solid tumours and haematological cancers.
The current focus of research includes compounds in three areas: signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition.In the EU, Taiwan, Mexico and Chile, afatinib is approved under the brand name GIOTRIF®, and in the U.S. under the brand name GILOTRIFTM for use in patients with distinct types of NSCLC. Afatinib is under regulatory review by health authorities in Asia and other countries. Nintedanib*, a triple angiokinase inhibitor is currently in Phase III clinical development in NSCLC and ovarian cancer. In the area of cell-cycle kinase inhibition, volasertib* is in phase III development for acute myeloid leukaemia.
Boehringer Ingelheim's oncology pipeline is evolving and demonstrates the company’s continued commitment to advance the disease area.
About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.
Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavours.
In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.
1. Ferlay J, ShinHR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. Int J Cancer. 2010;127:2893-917.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin2005;55:74-108.
3. Cancer Research UK. UK lung cancer incidence.CancerStats – Key Facts 2009. [Online] Available at: info.cancerresearchuk.org/cancerstats/types/lung/incidence/ [Last Accessed July 2013].
*Nintedanib and volasertib areinvestigational compounds and are not yet approved. Their safety and efficacy have not yet been fully established.
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Post by GodFather on Oct 30, 2013 10:08:23 GMT 5.5
New drug to help common bowel disease
An international team led by University of Adelaide researchers has identified the mechanism of pain relief of a new drug for treating Irritable Bowel Syndrome with Constipation (IBS-C), based on nonclinical studies, and quantified its effectiveness in pain relief in human trials. Published in the journal Gastroenterology, the study describes the pain mechanism of action for Linaclotide, a recently approved drug for the treatment of chronic abdominal pain and constipation in adult IBS-C patients.
IBS is a potentially debilitating condition with abdominal pain, bloating, diarrhoea and/or constipation. It affects up to 15% of western populations, costing millions of dollars annually in Australia alone in lost productivity and health care. Approximately one third of IBS patients are diagnosed as having IBS-C.
"This is a significant finding and very good news for IBS-C sufferers," says study leader Dr Stuart Brierley, NHMRC RD Wright Biomedical Fellow in the University's Nerve-Gut Research Laboratory. "IBS affects many people, particularly women, on a daily basis and has a significant impact on their quality of life. Abdominal pain is often the most troubling symptom to IBS patients and has been the most difficult symptom to treat.
"The drug is effective in relieving abdominal pain associated with IBS-C and is already available and registered for use by IBS-C patients in the USA and Europe. It is yet to go through the regulatory process in Australia."
The research is a collaboration between the Nerve-Gut Research Laboratory, (University of Adelaide) and Ironwood Pharmaceuticals Inc, the developers of Linaclotide. Linaclotide is a new class of medicine and is the only treatment for IBS-C currently registered with the European Medicines Agency; it is also the first prescription treatment available in over six years for adults with IBS-C in the US.
Linaclotide binds the receptor domain of guanylate cyclase-C on the inner lining of the intestines. It is marketed by Ironwood and Forest Laboratories Inc as Linzess® in the US and by Ironwood and Almirall SA as Constella® in Europe. Ironwood has partnerships through which it is conducting clinical trials of Linaclotide in China and Japan. Ironwood is exploring partnership opportunities for advancing Linaclotide in unpartnered territories, including Australia and New Zealand.
Dr Brierley, in the Nerve-Gut Research Laboratory, collaborated with Ironwood to further investigate how Linaclotide acts within the gastrointestinal tract to reduce abdominal pain. It had been shown to increase the secretion of fluids into the intestine and improve transit through the gastrointestinal tract. However, initial trials had shown that it also reduced abdominal pain associated with IBS-C, independently of its action on improving constipation.
Pre-clinical studies by the Nerve-Gut Research Laboratory showed that Linaclotide inhibits pain nerve endings in the intestine through a novel physiological pathway localised to the gastrointestinal tract. "The study also showed the analgesic effect translated into clinical findings in humans," says Dr Brierley. "IBS-C patients given the drug orally showed significant improvement in abdominal pain over those given placebo during a 26-week trial."
The research was funded by Ironwood, Forest and the National Health and Medical Research Council of Australia.
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Post by GodFather on Nov 1, 2013 16:32:18 GMT 5.5
Modified Botox could be used for the treatment of chronic pain and epilepsy
A team of 22 scientists from 11 research institutes led by Professor Bazbek Davletov, now at the University of Sheffield, created and characterised a new molecule that was able to alleviate hypersensitivity to inflammatory pain. The work is featured on the cover of the October 2013 issue of the scientific journal Bioconjugate Chemistry.
Professor Bazbek Davletov joined the Department of Biomedical Science in September last year from the Medical Research Council's Laboratory of Molecular Biology in Cambridge, where his team developed a new way of joining and rebuilding molecules.
By using elements of Clostridium botulinum and Clostridium tetani neurotoxins, commonly known as Botox and tetanus toxin respectively, the scientists were able to develop a molecule with new biomedical properties, without unwanted toxic effects.
While the Botox element is able to block neuronal communication - and therefore pain signals - for months, the tetanus component targets the central nervous system very effectively. The combination of the two elements is of great interest for neuroscience and can be applied to the treatment of several neurological disorders, particularly chronic pain conditions and epilepsy.
Botox and tetanus neurotoxins hold great promise for clinical applications, but their paralytic activity was a stumbling block until now. The team demonstrated that their newly engineered molecule is a potent non-paralysing neuronal blocker. Preclinical collaborative studies with Dr Enrico Ferrari at the University of Lincoln and Professor Stephen Hunt at University College London indicate usefulness of the new molecule for alleviation of inflammatory pain.
Professor Davletov added: "Currently painkillers relieve lingering pain only temporarily and often have unwanted side effects. A single injection of the new molecule at the site of pain could potentially relieve pain for many months in humans and this now needs to be tested. We hope that the engineered molecule could improve the quality of life for those people who suffer from chronic pain. We are now negotiating transfer of the technology to a major pharmaceutical company."
Professor Davletov's team in the Department of Biomedical Science is now working not only on neuronal blockers tailored for various neurological conditions but also on developing new cancer drugs.
Ferrari E, Gu C, Niranjan D, Restani L, Rasetti-Escargueil C, Obara I, Geranton SM, Arsenault J, Goetze TA, Harper CB, Nguyen TH, Maywood E, O'Brien J, Schiavo G, Wheeler DW, Meunier FA, Hastings M, Edwardson JM, Sesardic D, Caleo M, Hunt SP, Davletov B.
Synthetic self-assembling clostridial chimera for modulation of sensory functions.
Bioconjug Chem. 2013 Oct 16;24(10):1750-9. doi: 10.1021/bc4003103.
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Post by GodFather on Nov 25, 2013 13:23:15 GMT 5.5
Gene-silencing study finds new targets for Parkinson's disease
Scientists at the National Institutes of Health have used RNA interference (RNAi) technology to reveal dozens of genes which may represent new therapeutic targets for treating Parkinson's disease. The findings also may be relevant to several diseases caused by damage to mitochondria, the biological power plants found in cells throughout the body.
"We discovered a network of genes that may regulate the disposal of dysfunctional mitochondria, opening the door to new drug targets for Parkinson's disease and other disorders," said Richard Youle, Ph.D., an investigator at the National Institute of Neurological Disorders and Stroke (NINDS) and a leader of the study. The findings were published online in Nature. Dr. Youle collaborated with researchers from the National Center for Advancing Translational Sciences (NCATS).
Mitochondria are tubular structures with rounded ends that use oxygen to convert many chemical fuels into adenosine triphosphate, the main energy source that powers cells. Multiple neurological disorders are linked to genes that help regulate the health of mitochondria, including Parkinson's, and movement diseases such as Charcot-Marie Tooth Syndrome and the ataxias.
Some cases of Parkinson's disease have been linked to mutations in the gene that codes for parkin, a protein that normally roams inside cells, and tags damaged mitochondria as waste. The damaged mitochondria are then degraded by cells' lysosomes, which serve as a biological trash disposal system. Known mutations in parkin prevent tagging, resulting in accumulation of unhealthy mitochondria in the body.
RNAi is a natural process occurring in cells that helps regulate genes. Since its discovery in 1998, scientists have used RNAi as a tool to investigate gene function and their involvement in health and disease.
Dr. Youle and his colleagues worked with Scott Martin, Ph.D., a coauthor of the paper and an NCATS researcher who is in charge of NIH's RNAi facility. The RNAi group used robotics to introduce small interfering RNAs (siRNAs) into human cells to individually turn off nearly 22,000 genes. They then used automated microscopy to examine how silencing each gene affected the ability of parkin to tag mitochondria.
"One of NCATS' goals is to develop, leverage and improve innovative technologies, such as RNAi screening, which is used in collaborations across NIH to increase our knowledge of gene function in the context of human disease," said Dr. Martin.
For this study, the researchers used RNAi to screen human cells to identify genes that help parkin tag damaged mitochondria. They found that at least four genes, called TOMM7, HSPAI1L, BAG4 and SIAH3, may act as helpers. Turning off some genes, such as TOMM7 and HSPAI1L, inhibited parkin tagging whereas switching off other genes, including BAG4 and SIAH3, enhanced tagging. Previous studies showed that many of the genes encode proteins that are found in mitochondria or help regulate a process called ubiquitination, which controls protein levels in cells.
Next the researchers tested one of the genes in human nerve cells. The researchers used a process called induced pluripotent stem cell technology to create the cells from human skin. Turning off the TOMM7 gene in nerve cells also appeared to inhibit tagging of mitochondria. Further experiments supported the idea that these genes may be new targets for treating neurological disorders.
"These genes work like quality control agents in a variety of cell types, including neurons," said Dr. Youle. "The identification of these helper genes provides the research community with new information that may improve our understanding of Parkinson's disease and other neurological disorders."
The RNAi screening data from this study are available in NIH's public database, PubChem, which any researcher may analyze for additional information about the role of dysfunctional mitochondria in neurological disorders.
"This study shows how the latest high-throughput genetic technologies can rapidly reveal insights into fundamental disease mechanisms," said Story Landis, Ph.D., director of the NINDS. "We hope the results will help scientists around the world find new treatments for these devastating disorders."
This study was funded by the NINDS' and NCATS' Divisions of Intramural Research.
Reference: Hasson SA et al. "Genome-wide high-content RNAi screens identify regulators of parkin in selective mitophagy." Nature, November 24, 2013, DOI: 10.1038/nature12748
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Post by GodFather on Nov 26, 2013 14:01:26 GMT 5.5
Novartis highlights growth prospects driven by significant R&D pipeline progress and the expected increase in blockbuster treatments
Novartis has announced the launch of a USD 5 billion share buyback, reflecting the company's confidence in its long-term growth prospects, as well as its commitment to deliver strong shareholder returns. The buyback will start immediately and be executed over two years on the 2nd trading line. [*]
"Novartis has reached an inflection point, having fully integrated Alcon and reduced debt," said Joseph Jimenez, CEO of Novartis. "We are now further sharpening the execution of our strategy to strengthen shareholder value through science-based innovation in high-growth segments of healthcare where we have the global scale, competitive advantage and the right capabilities to win."
Novartis recently announced a definitive agreement to divest its blood transfusion diagnostics unit to Grifols for USD 1.7 billion. The sale enables Novartis to focus more sharply on its strategic businesses and is one result of the ongoing review of the diversified portfolio.
Novartis continues to focus on delivering shareholder returns in 2014 and 2015
Novartis re-confirms its capital structure aligned with a target rating of double-A as a reflection of the company's financial strength and discipline. Within this target rating, Novartis will allocate capital to a strong and growing dividend, value-creating bolt-on acquisitions and a USD 5 billion share buyback starting immediately, which reflects confidence in the company's growth prospects.
Novartis also announces it will continue to pursue an aggressive productivity agenda, which has offset generic erosion and growth investments over the past two years. Ongoing initiatives include leveraging scale in Procurement, consolidating Research sites around the world and optimizing the manufacturing footprint. These programs are expected to deliver approximately 3-4% of sales in productivity gains per year through 2015, and contribute to organic margin leverage.
Pharmaceuticals entering a new growth phase, driven by productive R&D engine
Pharmaceuticals, the largest division in the Novartis portfolio is preparing for a new growth phase, driven by an expanding blockbuster portfolio and an industry-leading pipeline. In addition to products with blockbuster status such as Lucentis, Gilenya, Afinitor and Tasigna, the Galvus group is expected to reach more than USD 1 billion in net sales by year end and there is the potential for a total of 14 or more blockbusters by 2018.
Novartis' productive R&D engine is reflected by the expanding blockbuster portfolio and, additionally, three FDA Breakthrough Therapy designations in 2013. This year, the company is thoroughly reviewing its assets, and has prioritized its development portfolio and established new platforms in areas where it sees significant potential for future sales growth - including Dermatology, Heart Failure, Respiratory and Cell Therapy - to complement the already successful Oncology business.
In Respiratory, for example, our comprehensive portfolio of products, Onbrez, Seebri and Ultibro, delivered through the Breezhaler inhalation device has the potential to address a large COPD population. Ultibro has recently been launched in Germany, the Netherlands and Japan.
In Dermatology, Pharmaceuticals has promising products under development including AIN457 (secukinumab). A regulatory application for the use of AIN457 for moderate-to-severe plaque psoriasis was submitted in the US and EU in October.
Oncology on track to grow every year through Glivec patent expiry
Within Pharmaceuticals, Novartis Oncology has continued to transform and rejuvenate its portfolio, and is on track to grow every year in the next five years despite loss of exclusivity for Glivec.
The Oncology pipeline includes an industry-leading 24 ongoing pivotal trials exploring 16 new products and indications. This acceleration of the development process is expected to lead to more approvals and sales by 2017 than previously projected. Expected news flow through 2015 includes results from 11 pivotal studies, including data on LDK378, an FDA Breakthrough Therapy, in ALK+ non-small cell lung cancer pre-treated with chemotherapy and crizotinib.
Innovation power focused on targeted and cellular therapies for cancer
Novartis' broad Oncology portfolio places the company at a strategic advantage in developing targeted and cellular therapies, as it provides access to single agents and unique proprietary combinations that can target specific tumor mutations and potentially overcome resistance mechanisms. For example, in 2013, Novartis initiated multiple combination studies containing LEE011, BKM120, BYL719, LGX818 or MEK162 including the initiation of a Phase III trial in December in breast cancer for LEE011 in combination with letrozole.
In addition, Oncology's groundbreaking chimeric antigen receptor technology (CART) platform, which now has multiple programs in various stages of development, bridges targeted therapies and immunotherapy with the potential to revolutionize cancer treatment. CTL019, in particular, has shown promise in chronic lymphocytic leukemia and acute B-cell lymphocytic leukemia patients, and is being investigated in additional CARTs.
Alcon expected to deliver above-market growth
Since the merger in 2011, Alcon has been integrated into the Novartis Group and achieved cost synergies of USD 370 million. The division is now positioned to deliver above-market growth in the mid to high-single digits in constant currencies, due to Alcon's broad portfolio of new and innovative products addressing significant patient need.
Surgical is growing the fastest, and is expected to benefit from the launch of its next-generation cataract refractive suite including Centurion, which has the potential to transform refractive outcomes for cataract patients. In Ophthalmic Pharmaceuticals, loss of exclusivity on some brands is expected to have a near-term impact, with products such as Jetrea and Simbrinza presenting opportunities for mid-term growth. Vision Care, with the launch of Dailies Total1, is well-positioned with a broad innovative portfolio in contact lenses.
A winning strategy for shareholders
Novartis maintains a consistent emphasis on innovation, growth and productivity across its diversified healthcare portfolio as part of its long-term strategy. Now, with greater clarity around its capital structure and allocation priorities, sharpened focus on actively managing the portfolio, and capturing synergies across divisions, Novartis' strategy is aligned with shareholder interests.
About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 133,000 full-time equivalent associates and operate in more than 140 countries around the world.
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Post by GodFather on Nov 26, 2013 14:05:18 GMT 5.5
H5N1 vaccine approved by the U.S. FDA as pandemic influenza preparedness measure
GlaxoSmithKline plc (LSE/NYSE: GSK) announced that the U.S. Food and Drug Administration (FDA) has approved its pandemic Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (also referred to as Q-Pan H5N1 influenza vaccine) for the immunisation of adults 18 and older for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. GSK received notification of the FDA approval late Friday afternoon (22 November).
The Q-Pan H5N1 influenza vaccine is composed of monovalent, inactivated, split A/H5N1 influenza virus antigen and GSK's AS03 adjuvant. In clinical studies, the adjuvanted formulation stimulated the required immune response while using a smaller amount of antigen as compared to a formulation without adjuvant. This could translate to a greater number of doses available at the time of a pandemic.
"Supporting the U.S. Government's capability to help protect Americans against pandemics ranks among GSK's most important U.S. public-health responsibilities," said Bruce Innis, Vice President of Vaccines Development for GSK. "H5N1-related illness has thus far been rare, but life-threatening when it has occurred. GSK scientists approached this clinical development project driven by the recognition that the resulting vaccine might be needed in the future to help protect millions of Americans against pandemic flu illness."
GSK will make this vaccine available in the U.S. only if directed to by the Biomedical Advanced Development and Research Authority (BARDA) in the U.S. Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response. The GSK H5N1 pandemic influenza vaccine programme has been supported by a development contract (HHSO100200700029C) from BARDA.
Licensure of the Q-pan H5N1 influenza vaccine is supported by data generated in two pivotal clinical studies showing that the vaccine was immunogenic and generally well-tolerated. The efficacy of GSK’s seasonal influenza vaccine FluLaval® Quadrivalent in the prevention of influenza disease was also submitted as supportive information.
In clinical trials, the most common solicited local reactions and general adverse events were injection site pain and swelling, muscle aches, headache, fatigue, joint pain, shivering and sweating.
GSK's Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, has also received marketing authorisation in Europe and Canada under the brand names, Pumarix™ and Arepanrix™ H5N1, respectively.
More about the H5N1 influenza strain
Influenza caused by the H5N1 strain has thus far been rare. The U.S. Centers for Disease Control (CDC) has reported that more than 600 human H5N1 cases have been reported to WHO from 15 countries in Asia, Africa, the Pacific, Europe and the Near East since November 2003. Approximately 60 percent of individuals with documented H5N1 disease have died.
GSK - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.
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