February 3, 2012

Sarcopenia Predictive of Mortality in Cirrhosis

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For patients with cirrhosis being evaluated for liver transplant, sarcopenia linked to mortality

Last Updated: February 03, 2012.

FRIDAY, Feb. 3 (HealthDay News) -- In patients with cirrhosis being evaluated for liver transplantation, sarcopenia is associated with increased mortality and significantly lower median survival time, according to research published in the February issue of Clinical Gastroenterology and Hepatology.

Aldo J. Montano-Loza, M.D., of the University of Alberta Hospital in Edmonton, Canada, and colleagues conducted a study involving 112 patients with cirrhosis (mean age, 54 years) to quantify the incidence of sarcopenia among patients with cirrhosis undergoing evaluation for liver transplantation. The association between sarcopenia and patient prognosis and mortality was evaluated.

The researchers found that 40 percent of patients with cirrhosis undergoing evaluation for liver transplantation had sarcopenia. Of the factors studied, only Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, and sarcopenia were independently associated with increased mortality on multivariate analysis (hazard ratios, 1.85, 1.08, and 2.21, respectively). Patients with sarcopenia had a median survival time of 19 ± 6 months compared with 34 ± 11 months for those without sarcopenia. A low level of correlation was seen between the L3 skeletal muscle index and MELD and Child-Pugh scores (P = 0.5 and 0.1, respectively).

"Sarcopenia is a strong and independent predictor of mortality in cirrhosis," the authors write. "Sarcopenia does not correlate with degree of liver dysfunction evaluated with conventional scores (Child-Pugh and MELD)."

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Alanine Aminotransferase Levels ID Liver Disease Risk

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ALT can be used to separate those infected with HCV RNA from those at low risk of liver disease

Last Updated: February 03, 2012.

FRIDAY, Feb. 3 (HealthDay News) -- Alanine aminotransferase (ALT) levels can be used to discriminate between individuals infected with hepatitis C virus (HCV) RNA and those at low risk for liver disease (negative HCV RNA and hepatitis B surface antigen, low alcohol consumption, no evidence of diabetes, and normal body mass index and waist circumference), according to a study published in the February issue of Hepatology.

Constance E. Ruhl, M.D., Ph.D., of Social and Scientific Systems Inc. in Silver Spring, Md., and James E. Everhart, M.D., M.P.H., of the National Institutes of Health in Bethesda, Md., evaluated the ability of serum ALT activity to differentiate between those with and without liver disease among participants in the 1999 to 2008 U.S. National Health and Nutrition Examination Survey. Serum ALT activity was measured in 18,518 participants; of these, there were 259 cases positive for HCV RNA and 3,747 at low risk for liver injury.

The researchers found that the maximum correct classification was achieved at ALT of 29 and 22 IU/L for men and women, respectively. The cut-off for 95 percent sensitivity was ALT of 24 IU/L for men and 18 IU/L for women, while the cut-off for 95 percent specificity was 44 and 32 IU/L for men and women, respectively. For men and women, the area under the curve was 0.929 and 0.915, respectively. Application of the cut-offs with the best correct classification would identify abnormal ALT in 36.4 percent of men and 28.3 percent of women.

"In the current study, the implications were demonstrated of the application of various cut-offs of ALT to the identification of an important liver disease, hepatitis C, and the proportion of the population that would be considered abnormal," the authors write. "Based on results from this national sample, a high proportion of the U.S. population would have elevated ALT at a level necessary to detect a high proportion of persons with HCV."

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Roundwood Doctor Nicola leads Hepatitis C reseach

PIONEERING TEAM OF VIROLOGISTS BASED IN UNIVERSITY OF BIRMINGHAM

By MYLES BUCHANAN

Wednesday February 01 2012

A DOCTOR FROM Roundwood is leading pioneering research into Hepatitis C.

Dr. Nicola Fletcher is the head of a team of virologists from the University of Birmingham who found that the endothelial cells in the brain possess the four main protein receptors necessary for the blood-brain barrier to be targeted by HCV.

The findings, which are published in Research Highlights in the journal Nature Reviews Gastroenterology and Hepatology, show that cells other than liver hepatocytes can be vulnerable to HCV infection.

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that poses a global health problem. Infection leads to progressive liver disease and has been associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities.

Working with the Manhattan Brain Bank in New York, USA, the researchers, led by Dr. Fletcher, of the University's School of Immunity and Infection, detected HCV genomic material in the brains of four out of ten infected patients who posthumously donated brain and liver tissue.

The team went on to demonstrate in laboratory tests that brain cells isolated from the blood-brain barrier could be infected with HCV.

' This is the first report that cells of the central nervous system support HCV replication,' says corresponding author Professor Jane Mckeating, chair of molecular virology at the University of Birmingham. ' These observations could have clinical implications providing a reservoir for the virus to persist during antiviral treatment'

Dr. Fletcher was educated in St David' Secondary School in Greystones, University of Limerick, and UCD where she completed her PHD before moving to the University of Birmingham to progress her research into the Hepatitis C virus.

Speaking about the findings, she says, ' The endothelial cells make up the security system of the brain, a kind of bouncer at the door that keeps out undesirable elements. If this barrier is compromised all kinds of substances can gain access to the brain, which may explain the fatigue and other symptoms reported by Hcv-infected patients.'

The current standard of care for treating Hcv-infected patients is only partially effective, she says, so there is a considerable drive to develop agents that target viral specific enzymes as alternative therapies. 'We anticipate that such agents will be less able to cross the bloodbrain barrier compared to existing drugs. We believe our data provides a detailed mechanistic view of how an infectious agent can target the brain.' Dr. Fletcher's other passion in life in the UK is her award-winning flock of pedigree Jacob Sheep appropriately called the 'Sugarloaf Jacob Flock' which she keeps at her home in Roundwood.

- MYLES BUCHANAN

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Gilead Gains on Positive Data From Experimental Hepatitis C Drug

By Ryan Flinn - Feb 2, 2012 8:24 PM ET

Gilead Sciences Inc. (GILD), the drugmaker that acquired Pharmasset Inc. last month for its experimental hepatitis C treatments, gained in extended trading after saying one of the therapies produced positive clinical trial results.

Patients with genotype 1 hepatitis C -- the most common inNorth America -- had no detectable signs of the virus after four weeks on the drug, PSI-7977, Norbert Bischofberger, Gilead’s chief scientific officer, said today on the Foster City, California-based company’s earnings call. An earlier study of the medicine, gained in the $10.8 billion Pharmasset purchase, cured all patients with genotype 2 and 3.

Drugmakers including Gilead, Merck & Co., Vertex Pharmaceuticals Inc. and Bristol-Myers Squibb Co. (BMY), are striving to develop a new class of oral cures for hepatitis C to replace older drugs that require injections. Bristol-Myers recently agreed to spend $2.5 billion to buy Inhibitex Inc. (INHX) for its experimental hepatitis C therapies.

“It looks like Gilead will race ahead and continue to lead because its drug 7977 continues to support potential 100 percent cure rates,” Michael Yee, an analyst with RBC Capital Markets in San Francisco, said in an interview. “The data disclosed in genotype 1, an important population for which there was no good data yet, continues to show they can support a multibillion-dollar drug franchise with 7977.”

The drug was tested in combination with ribavirin, a medication currently used in treating the disease. The therapy was given to patients who hadn’t taken other drugs and those whose illness wasn’t helped by other treatments.

The company will present further data on the clinical trial at an infectious diseases conference next month in Seattle.

Gilead rose as much as 6.4 percent to $52.45 after closing at $49.31 in New York trading.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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CAMBRIDGE, Mass., Feb. 3, 2012 /PRNewswire/ -- Idenix Pharmaceuticals, Inc. (NASDAQ: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that it has received notification from the U.S. Food and Drug Administration (FDA) that the partial clinical hold on IDX184 has been removed and that the Company's 12-week phase IIb study evaluating IDX184 in combination with pegylated interferon and ribavirin (PegIFN/RBV) may continue. IDX184, the Company's lead product candidate for the treatment of hepatitis C virus (HCV) infection is a pan-genotypic oral nucleotide polymerase inhibitor, and has demonstrated a high barrier to resistance in vitro and potent antiviral activity in both preclinical and clinical studies. Recently announced interim phase IIb data demonstrated favorable antiviral activity and no serious adverse events.

"After review of the interim safety and antiviral activity results from the IDX184 phase IIb clinical trial, the FDA removed the partial clinical hold and has allowed us to continue enrollment of this study," Ron Renaud, President and Chief Executive Officer of Idenix, commented. "Importantly, this allows us to expand the phase IIb program and evaluate IDX184 in interferon-free combination regimens with other direct-acting antivirals. We are working toward beginning all-oral combination trials as quickly as possible."

About IDX184 Phase IIb Study

In July 2011, Idenix initiated enrollment of treatment-naive genotype 1 HCV-infected patients into a randomized, double-blind, parallel group phase IIb clinical trial of IDX184. The study features two treatment arms, either 50 mg or 100 mg of IDX184 administered once-daily for 12 weeks, each arm in combination with PegIFN/RBV. Study objectives include safety and tolerability, and antiviral activity endpoints. The FDA has agreed to truncate the study from 100 patients, as in the original protocol, to a total of 60 patients, and to expand the enrollment criteria.

About IDX184 Partial Clinical Hold

A clinical hold originally was issued in September 2010 as a result of three cases of elevated liver function tests observed during a drug-drug interaction study in healthy volunteers of the combination of IDX184 and IDX320, an investigational HCV protease inhibitor. Idenix reviewed available data and conducted additional preclinical studies. With the help of independent experts and an external safety committee, the Company concluded that the observed toxicity was likely caused by IDX320 and submitted all data to the FDA. At the beginning of 2011, the FDA removed a full clinical hold on IDX184, and the program was placed on partial clinical hold allowing the Company to initiate the 12-week phase IIb study for IDX184 in July 2011. In January 2012, Idenix submitted interim phase IIb data for the first 31 patients to the FDA, along with a recommendation from the independent Data Safety Monitoring Board to continue the study, and requested removal of the partial clinical hold on IDX184. The partial clinical hold has now been removed allowing the initiation of dosing of an additional 30 patients in the ongoing phase IIb clinical trial and the initiation of a broad phase IIb program with IDX184 in the coming months.

About IDX184

IDX184 is an unpartnered, novel, liver-targeted nucleotide prodrug of 2'-methyl guanosine, which includes Idenix's proprietary liver-targeting technology. This technology enables the delivery of nucleoside monophosphate to the liver, leading to the formation of high levels of nucleoside triphosphate, potentially maximizing drug efficacy and limiting systemic side effects with low, once-daily dosing.

About Idenix

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.

Forward-Looking Statements

This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the Company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the Company's potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of IDX184 or any other drug candidate; the successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C; the likelihood and success of any future clinical trials involving our drug candidates; and expectations with respect to funding of operations and future cash balances. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the Company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the Company's dependence on its collaboration with Novartis Pharma AG; changes in the Company's business plan or objectives; the ability of the Company to attract and retain qualified personnel; competition in general; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's quarterly report on Form 10-Q for the quarter ended September 30, 2011, as filed with the Securities and Exchange Commission (SEC) and in any subsequent periodic or current report that the Company files with the SEC.

All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change.

Idenix Pharmaceuticals Contacts:
Kelly Barry (617) 995-9033 (media)
Teri Dahlman (617) 995-9807 (investors)

SOURCE Idenix Pharmaceuticals, Inc.

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PRESS RELEASE

Feb. 3, 2012, 2:00 a.m. EST

PARIS, February 3, 2012 /PRNewswire via COMTEX/ -- 'SARAH' - a French national collaborative randomized controlled trial of radioembolization with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma is now open for recruitment

The start of SARAH, a new randomized controlled trial to directly compare the effectiveness of radioembolization with yttrium-90 resin microspheres (SIR-Spheres® microspheres; Sirtex Medical Limited, Australia) versus sorafenib (Nexavar®, Bayer HealthCare Pharmaceuticals, Germany), a systemic therapy that is the current standard of care for patients with non-surgical advanced hepatocellular carcinoma (HCC), was announced today by the principal investigator, Professor Valérie Vilgrain MD, PhD, Department of Radiology, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy and Université Paris Diderot, Sorbonne Paris Cité, France.

SARAH (SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma)is a Phase III multi-centre prospective randomized open-labelled trial, which aims to recruit 400 patients in France with advanced HCC (Barcelona Clinic Liver Cancer stage C) with or without portal vein thrombosis and no extrahepatic spread, who are ineligible for surgical resection, liver transplantation or radiofrequency ablation; or whose disease has progressed or recurred after previous therapies.[1]

The primary goal of the study will be to assess if radioembolization with yttrium-90 resin microspheres provides an increased survival benefit compared to sorafenib in patients with advanced HCC.

Professor Vilgrain said: "Around 20 specialist cancer centres throughout France will be involved in this trial. SIR-Spheres microspheres were selected for the test arm of this collaborative trial, which is being promoted by the 'Assistance Publique - Hôpitaux de Paris'."

In patients with advanced HCC, sorafenib is now the standard treatment. Its use is associated with an increased median overall survival (from 8 to 11 months in the SHARP trial) but 80% of patients also experience treatment-related adverse events.

Selective Internal Radiation Therapy (SIRT), also known as radioembolization, is a novel treatment for inoperable liver cancer that delivers high doses of radiation directly to the site of tumours. It is a minimally-invasive treatment, in which millions of radioactive SIR-Spheres microspheres (diameter between 20-60 microns) are infused via a catheter into the liver, where they selectively target liver tumours with a dose of internal radiation up to 40 times higher than conventional radiotherapy, while sparing healthy tissue. There is a growing interest in radioembolization using yttrium-90 resin microspheres in this patient population, based on a substantial number of open-label single-group studies as well as a large multi-centre European analysis[2] of the long-term outcomes related to survival and safety of radioembolization using SIR-Spheres microspheres in patients with inoperable HCC. In 13 open-label single-group studies totalizing 400 patients with advanced HCC, the combined estimation of the median overall survival after radioembolization with yttrium-90 microspheres was of 15 months (min-max:7 to 27 months).

SIR-Spheres microspheres are approved for use in Australia, the European Union (CE Mark), New Zealand, Switzerland, Turkey and several other countries including in Asia (e.g. India, Korean, Singapore and Hong Kong) for the treatment of unresectable liver tumours. SIR-Spheres microspheres are also indicated in the U.S. for the treatment of non-resectable metastatic liver tumours from primary colorectal cancer in combination with intra-hepatic artery chemotherapy using floxuridine.

Professor Vilgrain said that: "The SARAH trial is testing the hypothesis that radioembolization using yttrium-90 resin microspheres can increase the median overall survival with fewer side effects and/or a better quality of life in comparison with sorafenib. We hope that the results of this study will help improve the prognosis for these difficult to treat patients".

About Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs in people whose livers have become severely damaged or cirrhotic, due to conditions such as hepatitis and alcoholism. It is one of the ten most-common cancers in the world, with nearly 750,000 cases diagnosed annually, and the third-leading cause of cancer deaths.[3] It occurs with greatest frequency in regions where viral hepatitis B or C aremost often diagnosed, such as in Asia Pacific and Southern Europe.

Hepatocellular cancer can be cured by surgery, either by resecting the diseased parts of the liver, or by transplantation with a liver from a healthy donor. These interventions, however, are inappropriate for the great majority of patients, whose survival may range from a few months to two or more years depending largely on the state of their liver at the time of their diagnosis and the extent of tumour invasion.

References:

SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma (SARAH): http://clinicaltrials.gov/ct2/show/NCT01482442.

Sangro B, Carpanese L, Cianni R et al on behalf of European Network on Radioembolization with yttrium-90 resin microspheres (ENRY). Survival after [90]Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: A European evaluation. Hepatology 2011; 54: 868-878.

GLOBOCAN. Liver Cancer Incidence and Mortality Worldwide in 2008. http://globocan.iarc.fr/factsheets/cancers/liver.asp accessed 28 June 2011.

SOURCE Sirtex Medical Limited

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