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Robinson J.G.,University of Iowa | Farnier M.,Point Medical | Krempf M.,University of Nantes | Bergeron J.,Clinique des Maladies Lipidiques de Quebec | And 9 more authors.
New England Journal of Medicine | Year: 2015

Background: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. Methods: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Results: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P = 0.02). Conclusions: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.) Copyright © 2015 Massachusetts Medical Society. Source

Regeneron Pharmaceuticals, Institute For Research In Biomedicine Irb and Yale University | Date: 2013-11-05

Genetically modified non-human animals are provided that may be used to model human hematopoietic cell development, function, or disease. The genetically modified non-human animals comprise a nucleic acid encoding human IL-6 operably linked to an IL-6 promoter. In some instances, the genetically modified non-human animal expressing human IL-6 also expresses at least one of human M-CSF, human IL-3, human GM-CSF, human SIRPa or human TPO. In some instances, the genetically modified non-human animal is immunodeficient. In some such instances, the genetically modified non-human animal is engrafted with healthy or diseased human hematopoietic cells. Also provided are methods for using the subject genetically modified non-human animals in modeling human hematopoietic cell development, function, and/or disease, as well as reagents and kits thereof that find use in making the subject genetically modified non-human animals and/or practicing the subject methods.

News Article
Site: http://cen.acs.org/news/ln.html

Capitalizing on continued drug industry interest in CRISPR/Cas9 technology, the gene-editing therapy start-up Intellia Therapeutics has formed a new partnership and is preparing for an initial public offering (IPO) of stock. Last week, Cambridge, Mass.-based Intellia signed a licensing and collaboration deal with Regeneron Pharmaceuticals. The partners will develop both the underlying CRISPR/Cas9 technology and in vivo therapies against as many as 10 targets. About half the targets will be diseases—such as the protein-accumulation disorder . . .

Gusarova V.,Regeneron Pharmaceuticals | Alexa C.A.,Regeneron Pharmaceuticals | Na E.,Regeneron Pharmaceuticals | Stevis P.E.,Regeneron Pharmaceuticals | And 8 more authors.
Cell | Year: 2014

Summary Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought "betatrophin" that could control pancreatic beta cell proliferation. However, studies of Angptl8-/- mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8-/- mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles plasma triglyceride levels, but does not alter beta cell expansion nor glucose metabolism. These data indicate that ANGPTL8 does not play a role in controlling beta cell growth, nor can it be given to induce such expansion. The findings that plasma triglyceride levels are reduced by Angptl8 deletion and increased following ANGPTL8 overexpression support the possibility that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia. © 2014 Elsevier Inc. Source

News Article
Site: http://news.yahoo.com/science/

A sign is seen at an AstraZeneca site in Macclesfield, central England May 19, 2014. REUTERS/Phil Noble CAMBRIDGE, England (Reuters) - AstraZeneca, working with genome pioneer Craig Venter, is launching a massive gene hunt in the most comprehensive bet yet by a pharmaceutical firm on the potential of genetic variations to unlock routes to new medicines. The initiative, announced on Friday, involves sequencing up to 2 million human genomes - the complete set of genetic code that acts as the software of life - including 500,000 DNA samples collected by AstraZeneca in global clinical trials. Financial details of the 10-year project were not disclosed but Mene Pangalos, head of early drug development, said the company would be investing "hundreds of millions of dollars". AstraZeneca aims to identify rare genetic mutations involved in every kind of disease by scanning DNA from volunteers who agreed to have their genomes sequenced and to provide access to detailed medical records. The project is made possible by a dramatic fall in the cost of genetic sequencing. It took government-funded scientists $3 billion and 13 years to sequence the first human genome by 2003. Today, it costs around $1,000 and takes just three days. AstraZeneca will work with Venter's U.S. company Human Longevity Inc (HLI), which will sequence the genomes, including 1 million from HLI's database, and use machine-learning software to find patterns in genetic variations. The British group, which is establishing an in-house Centre for Genomics Research in Cambridge, where it is relocating its global headquarters, has also partnered with the Wellcome Trust Sanger Institute and Finland's Institute for Molecular Medicine. AstraZeneca is not the first drugmaker to start amassing troves of human DNA in this way but Venter, one of the first scientists to sequence the human genome, said it was the biggest commitment to date by any pharmaceutical company. Regeneron Pharmaceuticals signed a deal with Pennsylvania's Geisinger Health System two years ago to sequence partial genomes of some 250,000 volunteers, while Roche's Genentech unit signed a deal last year for HLI to sequence tens of thousands of genomes. "The big thing here is the magnitude of what we are trying to do," Pangalos said. "This takes it to a completely different level and I think it is going to be relevant of every therapeutic area." Until now, the field of genomics has largely failed to live up to the hype of hoped-for medical breakthroughs, although more recently genetic understanding has been crucial in the development of some cancer treatments. Now, thanks to industrial-scale sequencing and advances in gene editing that allow scientists to quickly test the effects of genetic variations, progress is expected to accelerate. Venter believes it could also unleash a new era of forensics, with HLI trying to predict what people might look like from their DNA. AstraZeneca’s decision to embed genomics across its research and development follows a push last year by the company to expand gene testing into areas including heart disease and asthma. “I believe we really have finally turned the corner and genomics will become central in drug development efforts,” said David Goldstein, a genetics expert from Columbia University, who chairs AstraZeneca’s Genomics Advisory Board.

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