December 19, 2013

Protein links liver cancer with obesity, alcoholism, and hepatitis

PUBLIC RELEASE DATE:19-Dec-2013

Contact: Jennifer Brown
jennifer-l-brown@uiowa.edu
Public Library of Science

A new study identifies an unexpected molecular link between liver cancer, cellular stress, and risk factors for developing this cancer – obesity, alcoholism, and viral hepatitis. In the study by University of Iowa researchers and published in the journal PLOS Genetics, researchers show that a protein called CHOP, which had previously been thought to generally protect against cancer, actually promotes liver cancer in mice.

Obesity, alcoholism, and chronic hepatitis all increase the risk of getting liver cancer, the third leading cause of cancer death worldwide. There are few good treatment options for advanced liver cancer and rates of the disease have doubled in the U.S. in the past 20 years, driven in part by increasing obesity.

Obesity, alcoholism, and viral hepatitis also cause cellular stress and induce expression of CHOP, a transcription factor that is known to promote cell death. The study shows that in mice, despite its role in cell death, CHOP is actually elevated in cancerous liver cells. Furthermore, mice without CHOP are partially protected from liver cancer, developing fewer and smaller tumors than the normal mice in response to liver cancer-causing drugs. Tissue samples from human patients show that CHOP is also elevated in human liver tumors compared to surrounding non-tumor tissue from the same patients.

Having implicated CHOP as a contributing factor in liver cancer associated with obesity, alcoholism, and hepatitis, the UI team plans to identify the other proteins that partner with CHOP to promote liver cancer. A better understanding of this biological pathway may lead to targets for therapies to better treat liver cancer.

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PLoS One. 2013 Dec 11;8(12):e83382. doi: 10.1371/journal.pone.0083382.

Sasaki Y1, Ohfuji S2, Fukushima W2, Tamori A3, Enomoto M3, Habu D4, Iwai S3, Uchida-Kobayashi S3, Fujii H3, Shiomi S5, Kawada N3, Hirota Y2.

Abstract

INTRODUCTION: To date, there have been no prospective studies examining the effect of coffee consumption on serum alanine aminotransferase (ALT) level among individuals infected with the hepatitis C virus (HCV). We conducted a hospital-based cohort study among patients with chronic HCV infection to assess an association between baseline coffee consumption and subsequent ALT levels for 12 months.

MATERIALS AND METHODS: From 1 August 2005 to 31 July 2006, total 376 HCV-RNA positive patients were recruited. A baseline questionnaire elicited information on the frequency of coffee consumption and other caffeine-containing beverages. ALT level as a study outcome was followed through the patients' medical records during 12 months. The association between baseline beverage consumption and subsequent ALT levels was evaluated separately among patients with baseline ALT levels within normal range (≤45 IU/L) and among those with higher ALT levels (>45 IU/L).

RESULTS: Among 229 patients with baseline ALT levels within normal range, 186 (81%) retained normal ALT levels at 12 months after recruitment. Daily drinkers of filtered coffee were three times more likely to preserve a normal ALT level than non-drinkers (OR=2.74; P=0.037). However, decaffeinated coffee drinkers had a somewhat inverse effect for sustained normal ALT levels, with marginal significance (OR=0.26; P=0.076). In addition, among 147 patients with higher baseline ALT levels, 39 patients (27%) had ALT reductions of ≥20 IU/L at 12 months after recruitment. Daily drinkers of filtered coffee had a significantly increased OR for ALT reduction (OR=3.79; P=0.034). However, in decaffeinated coffee drinkers, OR could not be calculated because no patients had ALT reduction.

CONCLUSION: Among patients with chronic HCV infection, daily consumption of filtered coffee may have a beneficial effect on the stabilization of ALT levels.

PMID: 24349501 [PubMed - in process]

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FDA Hepatitis Update - New PegIntron Selectdose

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

On December 18, 2013, FDA approved a new single-use, dual-chamber pre-filled pen injector, PegIntron Selectdose (peginterferon alfa-2b), with recommendations for dose reductions, an updated Medication Guide and Instructions for Use (IFU).

The full revised label, including Instructions for Use with the Selectdose single-use pre-filled pen can be found at Drugs@FDA.

Healthcare providers should show patients how to prepare and inject PegIntron properly using the Selectdose pre-filled pen before it is used for the first time. Patients should make sure they have the correct strength of Selectdose pre-filled penprescribed by their healthcare provider.

Patients should properly dispose of the pre-filled pen after use. Instructions for Disposal of used needles and pre-filled pens are provided in the "in the Instructions for Use.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

If you are interested in receiving information about a broader range of FDA topics, consider subscribing to the FDA Patient Network News, a twice monthly newsletter containing FDA-related information on a variety of topics, including new product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings, proposed regulatory guidances and opportunity to comment, and other information of interest to patients and patient advocates.

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PRESS RELEASE

Dec. 19, 2013, 8:01 a.m. EST

NORCROSS, Ga., Dec 19, 2013 (GLOBE NEWSWIRE via COMTEX) -- Galectin Therapeutics Inc. GALT +4.65% , the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today announced that new preclinical data show its leading galectin-inhibiting drugs - GR-MD-02 and GM-CT-01 - demonstrate positive therapeutic effects on nonalcoholic steatohepatitis (NASH, or fatty liver disease) with fibrosis. Results were published in an article titled "Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors" in the peer-reviewed, open-access journal PLOS ONE.

In the study, NASH-induced mice were treated with GM-CT-01 and GR-MD-02 at two different points - early fibrosis and later more severe fibrosis. The studies evaluated twice-weekly, dose escalation of once weekly by intravenous administration, as well as evaluated different routes of administration including intravenous, subcutaneous and oral.

Results revealed that treatment with GR-MD-02 significantly improved NASH activity and reduced fibrosis including prevention of accumulation of collagen and/or reduced accumulated collagen in the liver. Similar effects were seen with GM-CT-01 but with approximately four-fold lower potency than GR-MD-02. The data also show reduction in galectin-3 expression and other inflammatory biomarkers. The PLOS ONE article can be found online at http://dx.plos.org/10.1371/journal.pone.0083481

"There are currently no approved treatments for fatty liver disease with fibrosis, a major health problem in the United States. These preclinical findings add to our scientific understanding of the role galectin inhibitors play in the treatment of fatty liver disease," said Peter G. Traber, M.D., Chief Executive Officer, President and Chief Medical Officer, Galectin Therapeutics. "The results support our current Phase 1 clinical trial of GR-MD-02 and our long-term development programs for GM-CT-01 and GR-MD-02."

GM-CT-01 and GR-MD-02 are proprietary molecules that bind to and inhibit galectin proteins, predominantly galectin-3. Six of eight patients have been enrolled and infused in cohort 1 of a blinded Phase 1 clinical trial of GR-MD-02 for patients with NASH with advanced fibrosis. Enrollment continues and no serious adverse events have been reported. The Phase 1 first-in-man study is evaluating the safety, tolerability, pharmacokinetics and exploratory biomarkers for efficacy for single and multiple doses of GR-MD-02 when administered to patients with fatty liver disease with advanced fibrosis. Clinical data from the first cohort is expected early in 2014.

About Fatty Liver Disease with Advanced Fibrosis

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease, has become a common disease of the liver with the rise in obesity rates, estimated to affect nine to 15 million people, including children, in the U.S. Fatty liver disease is characterized by the presence of fat in the liver along with inflammation and damage in people who drink little or no alcohol. Over time, patients with fatty liver disease can develop fibrosis, or scarring of the liver, and it is estimated that as many as three million individuals will develop cirrhosis, a severe liver disease where liver transplantation is the only current treatment available. Approximately 6,300 liver transplants are done on an annual basis in the U.S. There are no drug therapies approved for the treatment of liver fibrosis.

About Galectin Therapeutics

Galectin Therapeutics GALT +4.65% is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com .

Forward Looking Statements

This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. These statements include those regarding preclinical data and the potential role for GR-MD-02 and GM-CT-01 in the treatment of liver fibrosis and cirrhosis in humans. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others, that our plans, expectations and goals regarding any preclinical data and potential therapeutic uses and benefits of our drugs and any future pre-clinical or clinical studies are subject to factors beyond our control. Future clinical studies may not begin or produce positive results in a timely fashion, if at all, and could prove time consuming and costly. Plans regarding development, approval and marketing of any of our drugs are subject to change at any time based on the changing needs of our company as determined by management and regulatory agencies. Regardless of the results of current or future studies, we may be unsuccessful in developing partnerships with other companies or obtaining capital that would allow us to further develop and/or fund any studies or trials. To date, we have incurred operating losses since our inception, and our ability to successfully develop and market drugs may be impacted by our ability to manage costs and finance our continuing operations. For a discussion of additional factors impacting our business, see our Annual Report on Form 10-K for the year ended December 31, 2012, and our subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

Source

Liver Int. 2013 Dec 8. doi: 10.1111/liv.12431. [Epub ahead of print]

Saab S, Lalezari D, Pruthi P, Alper T, Tong MJ.

Abstract

INTRODUCTION: It is controversial if obesity has an impact on overall survival after liver transplantation. The goal of this study was to determine if obesity impacts liver transplant recipient survival. Through subgroup analysis, we also evaluated different BMI thresholds and the confounding effect of ascites on survival.

METHODS: A systematic literature search from 1990 until July 2013. The main outcome was to evaluate the impact of obesity on survival in adult LT recipients. Dochotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CI).

RESULTS: Thirteen studies with a total 2,275 obese and 72,212 non obese patients were included in the analysis. The combined analysis showed no difference in mortality between control and increased weight patients (RR 0.97, 95% CI [0.82, 1.13], P=0. 66) at last follow up. Moreover, no differences in mortality were noted in subgroup analysis comparing different BMI thresholds. There was also no differences in survival when BMI was adjusted for ascites or in studies where the liver disease severity was similar. Obese patients had worse survival than non obese patients in pooled analysis of studies which had similar causes of liver disease (RR 0.69, 95% CI [0.52, 0.92] P= 0.01).

CONCLUSION: The results of our pools analysis suggest that BMI does not specifically impact patient survival. However, obese patients have worse survival when analysis was performed in studies whose cohorts of obese and non obese patients had similar causes of liver disease. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: Liver Transplantation, Obesity

PMID: 24313970 [PubMed - as supplied by publisher]

Source

Clin Infect Dis. 2013 Dec 13. [Epub ahead of print]

Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, van Seggelen WO, Hijdra RM, Cassagnol DG; for the New York Acute Hepatitis C Surveillance Network.

Abstract

Background. There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. Methods. We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV RNA level <5IU/mL at least 12 weeks after completing treatment. Results. In the telaprevir group, 84% (16/19) achieved SVR 12 versus 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. Conclusions. Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.

PMID: 24336914 [PubMed - as supplied by publisher]

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Breaking the cycle of obesity, inflammation and disease

PUBLIC RELEASE DATE:19-Dec-2013 Contact: Laura J. Williams
laurajw@umich.edu
734-615-4862
University of Michigan

Breaking the cycle of obesity, inflammation and disease

ANN ARBOR—Researchers at University of Michigan have illuminated an aspect of how the metabolic system breaks down in obesity. The findings provide additional evidence that a drug entering clinical trials at the university could reverse obesity, Type 2 diabetes and fatty liver disease in humans.

In a paper scheduled for online publication in the journal eLife on Dec. 24, Alan Saltiel, the Mary Sue Coleman Director of the Life Sciences Institute, explains how, in obesity, fat cells stop responding to hormones known as catecholamines that trigger them to expend more energy. However, the fat cells of obese mice treated with a drug called amlexanox regained sensitivity to catecholamines, burned the excess energy and returned to normal size.

Next month, scientists at U-M will begin a placebo-controlled clinical trial of amlexanox to test its efficacy as a drug for treating obesity and diabetes in humans. Formulations of amlexanox are prescribed in different international markets to treat asthma and canker sores.

Obesity leads to a state of chronic, low-grade inflammation in liver and fat tissue. Scientists believe that inflammation links obesity and insulin resistance via a pathway called NFkB, which is involved in the regulation of a range of cellular processes and activated in obesity.

Activation of NFkB increases the levels of a pair of genes, IKKε and TBK1, which in turn reduce the ability of certain receptors in the fat cells of obese mice to respond to catecholamines like adrenaline, "fat-burning" hormones generated by the sympathetic nervous system in response to stress.

"We've suspected that in obesity, fat cells become less sensitive to catecholamines such as adrenaline, and that this reduced sensitivity in turn reduces energy expenditure, but the details of this haven't been fully understood," Saltiel said.

High levels of IKKε and TBK1 also resulted in lower levels of a second messenger molecule called cAMP, which increases energy expenditure by elevating fat burning.

Amlexanox interfered with the two enzymes and restored sensitivity to catecholamine, allowing the fat cells to burn energy.

In research published in February 2013, Saltiel found that amlexanox reversed obesity, diabetes and fatty liver in mice. The forthcoming eLife paper explains in part how amlexanox works.

"There is considerable evidence to suggest that in states of obesity, adipose tissue becomes less sensitive to catecholamines because IKKε and TBK1 act as a sort of brake on metabolism, and that this reduced sensitivity in turn reduces energy expenditure," Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system of mice to burn more and possibly store less energy in response to catecholamines."

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Saltiel is the Mary Sue Coleman Director of the Life Sciences Institute, where his laboratory is located and all his research is conducted. He is also the John Jacob Abel Collegiate Professor in the Life Sciences and a professor of internal medicine and molecular and integrative physiology at the Medical School.

Other authors of the paper are Jonathan Mowers, Maeran Uhm, Shannon Reilly, Joshua Simon, Dara Leto, Shian-Huey Chiang and Louise Chang, all from U-M. Support for the research was provided by the Michigan Diabetes Research and Training Center.

Alan Saltiel Lab: http://www.lsi.umich.edu/facultyresearch/labs/saltiel

U-M Life Sciences Institute: http://www.lsi.umich.edu

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