April 5, 2011

Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

Gastroenterology. 2011 Mar 16. [Epub ahead of print]

Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK; EPIC(3) Study Group.

BCLC Group; Liver Unit, Hospital Clinic of Barcelona, University of Barcelona; IDIBAPS, Centro de Investigación Biomédica en Red de Hepatología y Enfermedades Digestivas, Barcelona, Spain.


BACKGROUND & AIMS: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC(3)) program.

METHODS: Data was analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n = 311) or no treatment (controls, n = 315) for a maximum period of 5 years, or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.

RESULTS: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b, compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI], 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b, compared with controls (HR, 1.564; 95% CI, 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event, compared with controls ( P =.016). There were no new safety observations.

CONCLUSIONS: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21419770 [PubMed - as supplied by publisher]


Metabolic Syndrome Identified as Risk Factor for Liver Cancer

Roxanne Nelson

April 5, 2011 (Orlando, Florida) — Metabolic syndrome is a known risk factor for diabetes and heart disease, but researchers now report that it might also place individuals at higher risk for the development of liver cancer.

According to data presented here at the American Association for Cancer Research 102nd Annual Meeting, metabolic syndrome is associated with an increased risk of developing hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

The authors found that 37.1% of patients with hepatocellular carcinoma and 29.7% with intrahepatic carcinoma had preexisting metabolic syndrome. Conversely, only 17.1% of individuals without cancer had metabolic syndrome.

"Given the high and increasing rates of obesity, the metabolic syndrome, and nonalcoholic fatty liver disease in the United States, this is a very important and timely study," said Lewis Roberts, PhD, who was approached by Medscape Medical News for independent comment. "It shows that the rates of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma are higher in individuals with the metabolic syndrome."

"It is important for physicians and other healthcare workers to be aware of these associations, as people with metabolic syndrome are not generally viewed as being at high risk for these cancers," explained Dr. Roberts, professor of medicine at the Mayo Clinic in Rochester, Minnesota.

Although the specific mechanism linking these 2 conditions is still undefined, Dr. Roberts pointed out that metabolic syndrome is associated with increased inflammation in the liver and other tissues. "Inflammation is an important cause of cell injury and genetic damage to cells; this is a potential link between the metabolic syndrome and both hepatocellular carcinoma and intrahepatic cholangiocarcinoma," he said.

There is an urgent need for more research in this area to further our understanding of the specific mechanisms that drive cancer development in individuals with metabolic syndrome and to determine whether there are low-risk methods that can be used to prevent cancer development, he added.

Incidence Rising in the United States

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the 2 most common histologic types of primary liver cancer.

"In the United States, hepatocellular carcinoma is by far the most common, and accounts for about 70% of all primary liver cancers, whereas intrahepatic cholangiocarcinoma accounts for about 17%," said lead author Katherine McGlynn, PhD, a senior investigator at the National Cancer Institute.

Dr. McGlynn also noted that liver cancers are far more common among racial/ethnic minorities in the United States, especially hepatocellular carcinoma. Compared with white Americans, the incidence among all racial/ethnic minorities is at least 2-fold higher. The incidence of both types of cancer is rising; since the early 1970s, the incidence of hepatocellular carcinoma has jumped 212%, and the incidence of intrahepatic cholangiocarcinoma has risen by about 85%.

Metabolic syndrome, which is a collection of symptoms characterized by increased fasting glucose level, central adiposity, dyslipoproteinemia, and hypertension, has been previously linked to hepatocellular carcinoma, she explained, but the magnitude of the association has not been investigated at the population level in the United States.

"By the early years of the 21st century, unfortunately, over a third of the population is thought to have metabolic syndrome," she said. "Unfortunately, the prevalence is higher in some racial/ethnic minorities. Mexican Americans have a prevalence of about 45%."

Significantly More Common

Dr. McGlynn and colleagues used the Surveillance, Epidemiology, and End Results Program (SEER)–Medicare linked database to identify all people 65 years and older who were diagnosed with histologically confirmed hepatocellular carcinoma and intrahepatic cholangiocarcinoma between 1993 and 2005.

A total of 3,649 hepatocellular carcinoma cases and 743 intrahepatic cholangiocarcinoma cases were identified, as were 195,953 individuals without cancer who met the study inclusion criteria.

The team found that metabolic syndrome was significantly more common among people who developed liver cancer. After adjustment for demographic features and other risk factors, metabolic syndrome remained significantly associated with an increased risk for hepatocellular carcinoma (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.96 to 2.31; P < .0001) and intrahepatic cholangiocarcinoma (OR, 1.56; 95% CI, 1.32 to 1.83; P < .0001).

Interventions Needed

As obesity rates continue to rise in the United States, so will the incidence of metabolic syndrome. Better interventions/methods are needed for initiating changes in diet and lifestyle, Dr. Roberts said.

Experts in the liver cancer field are very concerned that as efforts to limit the spread of hepatitis C and hepatitis B, currently the most common causes of liver cancer in the United States, are more and more successful, the metabolic syndrome and fatty liver disease will become the predominant causes of an increasing epidemic of liver and biliary cancers," he said.

"It is critical to initiate and support the necessary dietary and lifestyle interventions for preventing the development of metabolic syndrome, particularly in children and young adults," Dr. Roberts added.

American Association for Cancer Research (AACR) 102nd Annual Meeting: Abstract 945. Presented April 3, 2011.


Factors that Affect Risk for Hepatocellular Carcinoma and Effects of Surveillance

Clinical Gastroenterology and Hepatology

Article in Press

Ju Dong Yang, William S. Harmsen, Seth W. Slettedahl, Roongruedee Chaiteerakij, Felicity T. Enders, Terry M. Therneau, Lucinda Orsini, W. Ray Kim, Lewis R. Roberts

Received 9 December 2010; received in revised form 25 February 2011; accepted 21 March 2011. published online 04 April 2011.
Accepted Manuscript


Background & Aims
The incidence of hepatocellular carcinoma (HCC) in the United States is increasing. Surveillance might affect the stage at diagnosis and consequently the treatment options available for HCC. We evaluated risk factors for HCC, the proportion of cases detected via surveillance, tumor characteristics, treatment approaches, and overall patient survival in a referral center cohort.

The study included all patients diagnosed with HCC at the Mayo Clinic, Rochester, MN, from 2007 to 2009 (n=460). Clinical information was retrospectively abstracted from the medical record.

Hepatitis C virus (HCV, 36%), alcohol use (29%), and nonalcoholic fatty liver disease (NAFLD, 13%) were the most common risk factors for HCC. HCV was present in 56% of patients younger than 60. NAFLD was present in 19% of patients older than 60. HCC was detected during surveillance in 31% of patients. Patients with worse liver function were more likely to be on surveillance. Transarterial chemoembolization, surgical resection, and liver transplantation were the most common treatment approaches for HCC. Patients diagnosed with HCC during surveillance had less-advanced disease, were more likely to be eligible for potentially curative treatments, and had increased survival times ( P <0.001).

At a major US referral center, the predominant HCC etiologies were HCV, alcohol use, and NAFLD. HCCs were detected during surveillance in the minority of patients. HCCs detected during surveillance were of less-advanced stage and patients were more likely to receive treatment that prolonged their survival.

Keywords: Etiology, surveillance, treatment, survival


Merck, J&J’s New Hepatitis C Treatment Fetches $31,000 in France

By Naomi Kresge and Carol Matlack - Apr 4, 2011 4:15 PM ET
New hepatitis C drugs from Merck & Co. and Johnson & Johnson (JNJ) are being sold in France for 22,000 euros ($31,271) and more, a precedent some doctors say may limit access after the medicines are approved throughout Europe.
J&J and Vertex Pharmaceuticals Inc. (VRTX)’s telaprevir costs 22,000 euros under a French program for seriously ill patients for whom there is no other effective treatment on the market, according to patient association SOS Hepatites. Merck & Co. said its boceprevir costs 30,000 euros under the same program.

The price may drop once the drugs are approved for the broader market, Merck and J&J executives said. Still, the French model shows the new drugs may triple the cost of hepatitis C treatment, leaving England, Russia and eastern Europe likely to delay use or restrict which patients are allowed access, said Antonio Craxi, director of gastroenterology and internal medicine at the University of Palermo.

“It may be that we can’t use it at all until the price comes down,” Mark Thursz, professor of hepatology at Imperial College London, said in an interview at a conference in Berlin over the weekend. “It’s not the best economic environment to launch an expensive new drug.”

The U.K.’s National Institute for Health and Clinical Excellence may restrict the new drugs to patients who have tried existing treatments without success, Thursz said. The agency may also require genetic tests to determine whether patients are likely to respond to the medicines, he said at the meeting of the European Association for the Study of the Liver.

‘Triple the Cost’

Italy and Spain also may delay or restrict use, Craxi said. Italy spends about 350 million euros a year on existing hepatitis C treatments, he said. “If you triple the cost, that would be more than 1 billion euros,” he said.

Vertex fell 10 cents, or less than 1 percent, to $47.49 at 4 p.m. New York time in Nasdaq Stock Market composite trading. Merck rose 20 cents, or less than 1 percent, to $33.27 in New York Stock Exchange composite trading. J&J increased 66 cents, or 1.1 percent, to $60.15.

The new drugs are being reviewed by regulators at the European Medicines Agency. Both are scheduled for U.S. Food and Drug Administration hearings at the end of this month.

In France, telaprevir and boceprevir received special temporary authorization in December, under a program designed for seriously ill patients for whom there is no other effective treatment on the market, according to French pharmaceutical regulator AFSSAPS. This allowed the drugs to bypass the usual approval procedures, the regulator said.

500 Patients

About 500 patients are being treated in France now, said Michel Bonjour, spokesman for SOS Hepatites. The new drugs are prescribed together with the current standard therapy of interferon and generic ribavirin, and the total cost of a yearlong cycle of treatment may reach 45,000 euros to 70,000 euros per patient, Bonjour said in an interview. The cost is covered in full by France’s national health insurance program.

“It’s not a good indication of price elsewhere,” Patrick Bergstedt, senior vice president for vaccines and infectious diseases at Whitehouse Station, New Jersey-based Merck, said in an interview.

The very sick patients in the French program get 44 weeks of treatment with boceprevir, while a more typical course of therapy is 24 weeks to 32 weeks, he said. There’s a “high likelihood” the eventual commercial price for a course of treatment will be less than the 30,000 euros Merck charges under the French program, he said.

‘Cost Effective’

“It’s black and white that these drugs are cost- effective,” Bergstedt said. “The challenge will be how do you stratify treatment, and how do you use these drugs responsibly to ensure the patients with the greatest need are treated first.”

Vertex, based in Cambridge, Massachusetts, referred questions to partner J&J, which will market telaprevir in Europe. J&J hasn’t decided on a final price, said Isabelle Lonjon-Domanec, global medical affairs leader for telaprevir at the New Brunswick, New Jersey-based company’s Tibotec Therapeutics unit.

Patients take telaprevir for 12 weeks together with standard treatment, then continue on the older standard drugs for a total of six months to a year of therapy.

Both new hepatitis C drugs are protease inhibitors crafted from the same technologies that led to discoveries in HIV research. Used in addition to existing therapies, they boost the chance of a cure from half of patients to between two-thirds and three-quarters of those treated, studies have shown.

U.S. Pricing

In the U.S., the new drugs may be priced at $35,000 to $40,000, estimates Howard Liang, a Boston-based analyst at Leerink Swann & Co.

“A cure saves a lot of money down the road,” Liang said in an interview. “It’s a shock to physicians, but I think it can be justified because it’s a cure.”

Hepatitis C, spread through contact with infected blood, is a virus that often lingers as a chronic condition, causing nausea and exhaustion as it destroys the liver over the course of years or decades. About 170 million people are infected, according to the World Health Organization.

Meanwhile, the next generation of drugs with even higher cure rates and fewer side effects is likely to reach the market within three years, Liang said.

Swedish drugmaker Medivir AB (MVIRB) has said it expects to begin selling a competitor pill to be used with interferon by 2013. Boehringer Ingelheim GmbH, Gilead Sciences Inc. (GILD) and Bristol- Myers Squibb Co. are among a dozen companies aiming for drug cocktails to replace the existing interferon combination.

Looming competition leaves Merck, Vertex and J&J without much time to recoup their investment, said Charles Gore, president of the Geneva-based patient advocacy group World Hepatitis Alliance.

“There is no easy answer to this,” Gore said in an interview. “We’ve got to have a way to give people access but incentivize the drug companies to research in this area.”

To contact the reporters on this story: Naomi Kresge in Berlin at nkresge@bloomberg.net; Carol Matlack in Paris at cmatlack@bloomberg.net

To contact the editors responsible for this story: Phil Serafino at pserafino@bloomberg.net;


Cholesterol Regulator Plays Key Role in Development of Liver Scarring, Cirrhosis

Treated with a control substance, livers from normal and LXR-deficient mice appear identical and undamaged (top left and right). The bottom images show the greater degree of fibrosis (blue bands) in the livers of mice lacking LXRs (right) compared to normal mice (left) after liver injury. (Credit: UCLA)

ScienceDaily (Apr. 4, 2011) — UCLA researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role in the development of liver fibrosis -- the build-up of collagen scar tissue that can develop into cirrhosis. Cirrhosis, in turn, is a major cause of premature death and is incurable without a liver transplant.

Published in the March issue of the journal Gastroenterology, the study shows that liver X receptors (LXRs), master regulators of cholesterol, fat and inflammatory gene expression, also control the fibrosis-making cells of the liver, known as hepatic stellate cells.

In the face of chronic liver injury -- due to excess fat, chronic viral hepatitis or alcohol abuse, for example -- stellate cells become activated and launch an inflammatory and fibrotic cascade that eventually results in the build-up of collagen scar tissue in the liver.

LXRs, when stimulated, "turn on" several hundred genes that hold instructions to create proteins for carrying out bodily processes in cells, from transporting and excreting cholesterol to synthesizing fat in the liver. They have also been shown to suppress inflammatory processes in several contexts.

"Our work sets the stage for looking at new ways to modulate cholesterol and/or fat metabolism in order to have therapeutic potential for the treatment of fibrosing liver diseases," said lead author Dr. Simon Beaven, an assistant professor of digestive diseases at the David Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Peter Tontonoz, a professor of pathology and laboratory medicine at the Geffen School of Medicine and a Howard Hughes Medical Institute investigator.

Beaven noted that the recent rise in obesity has resulted in a surge in the prevalence of a condition known as fatty liver, which can be a precursor to fibrosis and chronic liver disease. Simple fatty liver, also known as non-alcoholic fatty liver disease, or NAFLD, is one of the most common reasons patients consult a liver doctor in the United States. Cirrhosis due to fatty liver is skyrocketing and within a decade may become the most common indication for liver transplantation.

Beaven said the need to find better treatments for liver disease is crucial.

"A 'holy grail' for liver researchers is to develop anti-fibrotic treatments that target activated stellate cells in order to slow or prevent the development of cirrhosis," Beaven said. "Our study offers the first detailed look at how LXRs specifically impact the activation of hepatic stellate cells and the subsequent development of liver fibrosis in animal models."

UCLA researchers have found that LXRs normally play a role in helping to reduce the collagen-producing actions of stellate cells when the cells are "activated" by liver damage. For the study, UCLA scientists first tested how activated stellate cells taken from mice would react when a chemical that induces LXR activity was added to the cell culture.

In stellate cells from normal mice, LXRs suppressed the inflammatory and fibrosis-promoting program. But in those taken from mice genetically lacking LXRs, that same program of genes significantly increased because the inhibitory effect of LXRs was no longer present.

"We showed that LXRs dampen stellate cell activation by repressing inflammatory and collagen-producing genes," Beaven said.

To further gauge the strength of the response, scientists took the medium from the cultures of LXR-deficient cells and added it to stellate cells from normal mice. These cells then showed a markedly exaggerated inflammatory and collagen-producing response, suggesting that LXR-deficient stellate cells are secreting signals to promote fibrosis.

The researchers noted that these experiments demonstrate that LXRs control a fibrotic response in stellate cells that can have a wide influence on neighboring cells.

The scientists also found that after replicating chronic liver injury, mice without LXRs had dramatically more liver fibrosis than normal mice.

"The genetic loss of LXRs rendered the mice susceptible to developing fibrotic liver disease," Beaven said.

But LXRs are also known to have important functions in the immune system. The researchers then wanted to know whether the effects they were seeing in animals were due to changes in stellate cell activity specifically or whether immune cells -- derived from bone marrow -- accounted for most of the effect. After extensive testing, the researchers found no differences

in the level of liver fibrosis among normal mice and animals lacking LXRs, suggesting that the contribution from the immune system was negligible.

"This finding, along with the cell culture studies, suggests that LXRs' influence on fibrosis most likely resides in altering stellate cell function in the liver," Beaven said. "This is a critical finding and opens an entire new field of study for stellate cell biologists."

Additional studies will further identify which genes in stellate cells are activated by LXRs and help researchers better understand the role of cholesterol metabolism in the fibrotic response.

This study was funded primarily by grants from the National Institutes of Health and the Howard Hughes Medical Institute. Collaborators from the University of Southern California were funded by core grants from the NIH and the Southern California Research Center for ALPD and Cirrhosis.

Other study authors included senior investigator Dr. Peter Tontonoz of the Howard Hughes Medical Institute; Kevin Wroblewski and Cynthia Hong from Tontonoz's lab; Jiaohong Wang and Hide Tsukamoto of the Southern California Research Center for ALPD and Cirrhosis, USC's Keck School of Medicine and the Department of Veterans Affairs Greater Los Angeles Healthcare System; and Steven Bensinger of the department of pathology at the David Geffen School of Medicine at UCLA.

Journal Reference:

1.Simon W. Beaven, Kevin Wroblewski, Jiaohong Wang, Cynthia Hong, Steven Bensinger, Hide Tsukamoto, Peter Tontonoz. Liver X Receptor Signaling Is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease. Gastroenterology, 2011; 140 (3): 1052 DOI: 10.1053/j.gastro.2010.11.053


Peregrine's PS-Targeting Antibody Significantly Improves Anti-Tumor Effect of Sorafenib in Models of Advanced Liver Cancer

Apr 05, 2011 08:00 ET

AACR Data Presentation Supports Phase I/II Investigator-Sponsored Clinical Trial in Advanced Liver Cancer

TUSTIN, CA and ORLANDO, FL--(Marketwire - April 5, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced that its phosphatidylserine (PS)-targeting antibody significantly enhanced the anti-tumor effects of sorafenib (Nexavar®) in models of hepatocellular carcinoma (HCC), with 69% less tumor growth compared to sorafenib alone. This study, one of four poster presentations on Peregrine's PS-targeting antibodies at the Annual Meeting of the American Association of Cancer Research (AACR), was the basis for initiating a Phase I/II investigator-sponsored trial (IST) evaluating the company's lead antibody bavituximab with sorafenib in patients with advanced HCC. Bavituximab is currently in three randomized Phase II clinical trials in lung cancer and pancreatic cancer and several ISTs for additional oncology indications.

"Our studies show that sorafenib more than doubles the amount of the immunosuppressive molecule PS exposed on the blood vessels of HCC tumors," said Philip E. Thorpe, Ph.D., professor of pharmacology at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "These data suggest that the growth-blocking mechanisms of sorafenib combined with the vascular-targeting and immune-reactivation mechanisms of bavituximab may offer additive anti-tumor effects for patients with HCC."

As presented today at AACR, tumor growth was 69% less for the group receiving Peregrine's antibody in combination with sorafenib than for the group receiving sorafenib alone (mean tumor weight of 127 mg versus 409 mg, n=10, p < 0.01) after 59 days of treatment in an animal model study. Immunofluorescence analysis showed that treatment with Peregrine's antibody in combination with sorafenib decreased tumor blood vessel density from 14.2% to 4.5% (p < 0.01), versus 10.3% (p < 0.05) for Peregrine's antibody or 8.4% (p < 0.01) for sorafenib alone.

A copy of the AACR poster is available at Peregrine's website at http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html.

About the Phase I/II HCC Investigator-Sponsored Trial

In an ongoing open-label Phase I/II trial, patients with advanced HCC are receiving bavituximab weekly and sorafenib (400 mg) twice daily, until disease progression or toxicity. Phase I of the trial is dose escalation (0.3, 1 or 3 mg/kg) to determine the maximum tolerated dose (MTD) and Phase II is expansion of the study at the MTD. Approximately 50 patients are being enrolled in this trial, which is being conducted at UT Southwestern Medical Center.

Primary objectives are to determine the MTD of bavituximab in patients with advanced HCC treated with sorafenib and the radiographic median time to progression. Secondary objectives include response rate, progression free-survival, overall survival, safety and tolerability. Further information about this trial is available at PeregrineTrials.com, UT Southwestern Medical Center Clinical Trials, and ClinicalTrials.gov.

About Peregrine's Investigator-Sponsored Trials (IST) Program

Peregrine's IST program offers oncologists the opportunity to conduct clinical trials using bavituximab in solid tumor indications.

About Bavituximab

Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.

About Hepatocellular Carcinoma (HCC)

According to the National Cancer Institute, primary liver and bile duct cancers are the sixth most common cause of cancer death in men, and ninth most common in women. Approximately 24,000 new cases of these two cancers are expected to be diagnosed this year in the United States, with approximately 19,000 deaths attributable to these forms of cancer. The most common risk factor for liver cancer is chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. Currently approved treatment options for HCC are surgery, radiation, chemotherapy, targeted therapeutics, tumor ablation, and tumor embolization.

Xiaoyun Cheng and Philip E. Thorpe, UT Southwestern Medical Center, Dallas, TX. Phosphatidylserine-targeting antibody combined with sorafenib has strong anti-tumor activity against human hepatocellular carcinomas in mice. In Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research (AACR); 2011 Apr 2-6; Orlando, FL. Abstract 2643.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.

Nexavar® (sorafenib) is a registered trademark of Onyx Pharmaceuticals/Bayer Healthcare.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from investigator-sponsored trials will not be consistent with results experienced in earlier clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended January 31, 2011. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256


EASL: Jennerex and Transgene Announce the Presentation of Positive Clinical Data of JX-594 in Patients With Liver Tumors

SAN FRANCISCO and ILLKIRCH, France, April 5, 2011 /PRNewswire/ -- Jennerex, Inc., a private clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class targeted oncolytic products for cancer, and Transgene (NYSE Euronext Paris: FR0005175080), a bio-pharmaceutical company specialized in the development of immunotherapeutic products, today announced that new data from Phase 1 and 2 clinical studies of JX-594 were presented in an oral presentation at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) over the weekend at the Internationales Congress Centrum in Berlin, Germany.

The data from abstract #LB-283, entitled "JX-594, A Targeted Multi-Mechanistic Oncolytic Poxvirus, is Well-Tolerated and Exhibits Anti-Tumor Activity in Patients with Primary Liver Cancer and Liver Metastases," were presented by Caroline Breitbach, Ph.D., director of translational research.

"We are pleased to present these data on JX-594 at the EASL meeting, as they provide further evidence that both primary liver cancer and metastases to the liver can be treated safely with JX-594, with transient flu-like symptoms being the most common adverse events. Anti-cancer activity continues to be clearly demonstrated in a broad spectrum of common solid tumor types," said David H. Kirn, M.D., president and chief executive officer of Jennerex.

"We look forward to reporting additional clinical results in patients with advanced liver cancer from two ongoing studies—a randomized Phase 2 trial of JX-594 evaluating survival across two dose groups, and a Phase 2 clinical trial evaluating JX-594 in combination with sorafenib," added Philippe Archinard, chairman and chief executive officer of Transgene.

Clinical Results

This presentation highlighted data from 35 patients with either primary liver cancer, known as hepatocellular carcinoma (HCC), or cancer metastases to the liver (including colorectal cancer, melanoma and renal cancer). All patients were given intratumoral (IT) injections (up to eight treatments) over the course of JX-594 therapy. Twenty-three patients (66%) exhibited significant tumor necrosis and responses by modified Choi criteria (decreased tumor density). Choi responses have also been documented in non-injected tumors, consistent with prior data on JX-594. Seven patients (20% of evaluable) also exhibited objective response by Response Evaluation Criteria in Solid Tumor (RECIST) criteria, including two complete responses upon long-term follow-up. Twenty patients (57%) had stable disease as defined by RECIST criteria.

About JX-594

JX-594 is a proprietary, engineered oncolytic virus that is designed to selectively target and destroy cancer cells. JX-594 is designed to attack cancer through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction, and the stimulation of the body's immune response against cancer cells (ie active immunotherapy). Phase 1 and Phase 2 clinical trials in multiple cancer types to date have shown that JX-594, delivered either directly into tumors or systemically, induces tumor shrinkage and/or necrosis and is well-tolerated by patients. Objective tumor response has been demonstrated in a variety of cancers including liver, colon, kidney, lung and melanoma.

Transgene holds an exclusive license to develop and commercialize JX-594 in Europe and neighboring countries. Green Cross Corporation, a leading company in the development, manufacturing, and commercialization of viral vaccines and other biological products, holds an exclusive license to develop and commercialize JX-594 in South Korea, and Lee's Pharmaceutical Ltd. holds an exclusive license to develop and commercialize JX-594 in China.

About Liver Cancer and Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related deaths world-wide with about 660,000 patients dying from the disease annually. Most HCC cases develop on the background of chronic liver cirrhosis; in regions with the highest incidence of HCC, East Asian and African countries, the majority of cases are related to hepatitis B; in developed Western countries and Japan the disease is commonly related to hepatitis C, heavy alcohol consumption and non-alcoholic fatty liver due to metabolic syndromes such as diabetes and obesity. There is accumulating evidence that the incidence of HCC is increasing in Western countries. Despite recent advances, the treatment of advanced HCC remains a significant unmet medical need with a median expected survival under current therapies of less than one year.

About Jennerex

Jennerex, Inc. is a clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer. The Company's lead product JX-594 is currently in two Phase 2 clinical trials in patients with primary liver cancer—an international, randomized, Phase 2 clinical trial, and a Phase 2 study of JX-594 in combination with sorafenib. Published studies designed to establish optimal dose levels and the safety profile of JX-594 have shown its ability to selectively target and cause destruction of a variety of common cancer types. JX-594 and other product candidates under development are designed to attack cancer tumors through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction and the stimulation of the body's immune response against the cancer. Jennerex is headquartered in San Francisco and has related research and development operations in Ottawa, Canada and Pusan, South Korea. For more information about Jennerex, please visit www.jennerex.com.

About Transgene:

Transgene, a member of the Institut Merieux Group, is a publicly traded French biopharmaceutical company dedicated to the development of therapeutic vaccines and immunotherapeutic products in oncology and infectious diseases, and has five compounds in clinical development: TG4010 and JX594 (TG6006) having completed initial phase II trials, TG4001 in phase IIb trial, TG4040 in phase II trial and TG4023 in phase I trial. Transgene has concluded strategic agreements for the development of two of its immunotherapy products, an option agreement with Novartis for the development of TG4010 to treat various cancers, and an in-licensing agreement with US-based Jennerex Biotherapeutics, Inc., to develop and market JX594 (TG6006), an oncolytic product.

Transgene has bio-manufacturing capacities for viral-based products. Additional information about Transgene is available on the internet at http://www.transgene.fr/

Cautionary note for Transgene regarding forward-looking statements

This press release contains forward-looking statements referring to the joint clinical testing and development and commercial potential of JX-594. Clinical testing and successful product development and commercialization depend on a variety of factors, including the timing and success of future patient enrolment, the risk of unanticipated adverse patient reactions, regulatory approval and the level of demand for the product by the medical community. Results from future studies with more data may show less favorable outcomes than prior studies, and there is no certainty that product candidates will ever demonstrate adequate therapeutic efficacy or achieve regulatory approval or commercial success. In addition, forward-looking statements regarding product development, testing and marketing costs are by the nature subject to uncertainties as a result of unforeseen difficulties and expenses which may arise, and future product development costs may exceed current expectations. For further information on the risks and uncertainties involved in the testing and development of Transgene's product candidates, see Transgene's Document de Reference on file with the French Autorite des marches financiers on its website at http://www.amf-france.org/ and Transgene's website at http://www.transgene.fr/.

SOURCE Jennerex, Inc.



EASL Issues Clinical Practice Guidelines for Management of HCV

Daniel M. Keller, PhD

April 4, 2011 (Berlin, Germany) — Here at the opening session of the European Association for the Study of the Liver (EASL) 46th Annual Meeting, new guidelines were announced to help healthcare providers, patients, and interested individuals make decisions about the management of patients with acute and chronic hepatitis C virus (HCV) infections.

The guidelines encompass all aspects of the diagnosis and treatment of chronic HCV infection and address the use of diagnostic, therapeutic, and preventive techniques. They are the fifth in a series that the EASL has issued for liver diseases.

As evidenced by a wealth of clinical trial presentations that are being made here at the conference on new drugs in development to treat HCV, it is expected that many more treatments will be licensed in the next few years.

However, the guidelines issued here are restricted to therapies that have been approved at the time of publication. EASL has committed to update the guidelines on a regular basis upon approval of additional therapies.

Antonio Craxi, MD, professor of gastroenterology and internal medicine at the University of Palermo in Italy, and director of gastroenterology and hepatology at the university's Academic Department of Internal Medicine, coordinated the development of the guidelines. He discussed them in a news conference and said that part of the rationale for them is to set standards of diagnosis and treatment for specific patient profiles. They were developed by an expert panel that reviewed the scientific literature on the subject through December 2010. If clinical data were unavailable, expert experience and opinion were included.

The guidelines comprise sections on diagnosis, therapy, follow-up to therapy, measures to improve treatment success rates, and factors to consider when deciding on retreatment if therapy has failed.

Dr. Craxi emphasized that history and physical examination of the patient must be part of diagnosis, and that diagnosis cannot rely solely on serology that identifies anti-HCV antibodies or the level of HCV RNA in the blood.

"We had to . . decide on a very crucial point — whether a biopsy was still necessary to assess the severity of liver disease," Dr. Craxi said.

Although biopsy remains the reference method for assessing the degree of fibrosis, most patients dislike it, and it carries risk for complications. "It won't be acceptable to have a liver biopsy as a prerequisite for all treatment," he said, noting that it can usually be dispensed with for HCV genotypes 2 and 3, which are easier forms of the virus to eradicate with current therapy. And a biopsy is not always necessary for the more difficult-to-treat genotypes 1 and 4, since other methods such as transient elastography (FibroScan) and serum biomarkers are available to determine the degree of liver fibrosis.

Eradication of HCV Infection Is Therapeutic Goal

Eliminating virus from the body can prevent complications such as fibrosis, cirrhosis, liver cancer, and death. The desired end point of therapy is a sustained virological response, determined by undetectable HCV RNA in the blood 24 weeks after the end of therapy, Dr. Craxi noted.

The current standard approach is treatment with a combination of pegylated interferon alfa plus ribavirin. The University of Palermo investigator said large studies have shown that the 2 commercially available pegylated interferons are equivalent, and neither is recommended over the other.

He pointed out that the new guidelines consider the virological response to pegylated interferon/ribavirin to guide therapy, taking into account the speed of response and the degree of viral suppression. "For the first time, there is a clear statement that patients with a rapid response and with genotype 1 can be treated for 24 weeks [and that treatment can be extended] beyond 24 weeks for patients who have a delayed viral response."

Separate decision maps in the published guidelines, which will appear in the Journal of Hepatology, delineate response-guided therapy for genotypes 1 and 4 and for genotypes 2 and 3.

Previous American guidelines were issued more than 5 years ago, Dr. Craxi noted, and they did not involve response-guided therapy. Additionally, ribavirin dosage adjustment according to patient weight is now recommended, since heavier weight adversely affects the response to therapy.

The expert panel made recommendations for the follow-up of untreated patients with or without cirrhosis and for the retreatment of patients for whom previous therapy failed. Dr. Craxi said that patients with resistant disease might respond to some of the new small-molecule drugs currently in development, and it might be worthwhile to delay treatment for some of them until the new drugs are available, depending on their current state of health.

Mark Thursz, MD, EASL vice secretary and professor of hepatology at Imperial College, London, United Kingdom, noted that not recommending a liver biopsy for every patient is an important development for patients. "It's no longer necessary for every patient. In fact, it's probably only appropriate when there's a doubt about the contribution of different diseases," such as heavy alcohol consumption and HCV, or obesity and HCV. Response-guided therapy can also be positive for patients, sparing some of them unnecessary adverse effects if they can be treated for a shorter time. It should have a positive economic impact, as well, he noted.

Dr. Thursz said he reviewed the guidelines before publication but was not involved in their development.

Dr. Craxi reports receiving research support and lecture fees from, and taking part in clinical trials for, Roche, MSD, Siemens, and Abbott. Dr. Thursz has disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) 46th Annual Meeting: Opening session. Presented March 31, 2011.


Download PDF: Management of Hepatitis C Virus Infection 1.41 mb

Potential hepatitis C drug's step forward

April 4th, 2011 (PhysOrg.com) -- Successful initial trial for INX-189, originally synthesised in Cardiff

Inhibitex, the US biopharmaceutical company working on potential anti-viral drugs with Prof Chris McGuigan’s laboratory in the Welsh School of Pharmacy, has just announced the successful conclusion of the initial phase 1 trials of INX-189 in hepatitis C patients.

This drug, first synthesised less than three years ago in the laboratory in the Welsh School of Pharmacy, is active against Hepatitis C. This disease affects some 170 million individuals worldwide (3 per cent of the human population) and current treatment is unsatisfactory.

In the current trial, around 50 HCV patients received either a daily oral dose of INX-189, ranging from 3 mg to 100 mg, in some cases in combination with the current drug Ribavarin, for 7 days. The Company plans to present detailed results from this trial during a future scientific meeting. Preliminary data from the trial includes:

-- No serious adverse events.

-- No drug related events that increase with dose.

-- Dose-responsive increases in viral load reduction in the range 9-100mg per day, at both 3 days and 7 days.

-- Ribavirin (100mg once a day) is synergistic with INX-189 at 25mg daily.

Professor McGuigan, who is also a member of the Board of Directors of Inhibitex, warmly welcomed this news, saying: "The outcome of these multiple dose studies in patients on INX-189 are exciting and continue to show the effectiveness of the drug in patients with hepatitis C. We now need to continue with a full phase II clinical study. INX-189 has today taken a major step closer to becoming a much needed new drug for hepatitis C infection."

For recent scientific papers describing the development of INX-189 see:

Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus
Christopher McGuigan, Karolina Madela, Mohamed Aljarah, et al.
Bioorganic & Medicinal Chemistry Letters 20 (2010) 4850-4854


Phosphoramidate ProTides of 2’-C-Methylguanosine as highly potent inhibitors of hepatitis C virus. Study of their in vitro and in vivo properties.
C. McGuigan, A. Gilles, K. Madela, M. Aljarah, et al.
J. Med. Chem., 2010, 4949-4957.

Provided by Cardiff University


EASL: Abbott and Enanta Present Positive 12-Week Results and 3-Day Resistance Data From Phase 2 Study of ABT-450/r for Treatment of Hepatitis C

ABBOTT PARK, Ill., and WATERTOWN, Mass., April 4, 2011 /PRNewswire/ -- Abbott (NYSE: ABT) and Enanta Pharmaceuticals today announced 12-week results from a Phase 2 study of ABT-450/r, an investigational, oral protease inhibitor being developed for the treatment of hepatitis C (HCV) infection. Study results show that 92 percent (22 of 24) of patients taking ABT-450/r once daily, combined with standard of care, achieved complete early virologic response (HCV RNA levels <25 IU/mL) at 12 weeks. Results were presented at the European Association for the Study of Liver Disease (EASL) annual meeting in Berlin.
Key findings:

• At week 12, 92 percent of patients receiving ABT-450/r (ABT-450 with 100 mg of ritonavir to support once-daily dosing) in combination with standard of care (SOC) – pegylated interferon alpha and ribavirin (pegIFN/RBV) – achieved HCV RNA <25 IU/mL

• In a separate analysis of 3-day resistance data, ABT-450/r dosed at 200/100 mg appeared to more consistently suppress the emergence of ABT-450-associated resistant variants than the 50/100 mg and 100/100 mg doses

• Previously presented 3-day and 4-week results from the study had suggested the ABT-450/r demonstrated significant antiviral activity in treatment-naive adults

• After three days, treatment with ABT-450/r alone resulted in 4-log (10,000-fold) mean reductions of HCV RNA, across the three dose ranges of ABT-450 (50 mg, 100 mg, 200 mg, once-daily dosing)

"A significant number of HCV patients are unable to begin treatment with peginterferon and ribavirin, and for those that do begin treatment, more than 50 percent will not be cured," said Fred Poordad, M.D., chief of hepatology at the Liver Disease and Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and one of the investigators for the study. "These results suggest that ABT-450/r could be an important component in combination therapy approaches to treating HCV."

"Abbott is working to transform treatment options for patients with HCV infection by investigating ways to simplify treatment and increase cure rates," said Scott Brun, M.D., divisional vice president, infectious disease development, Abbott. "We will continue to explore the use of ABT-450/r and our other investigational HCV treatments in a variety of patient populations and combinations, with and without pegylated interferon alpha."

"We continue to be encouraged by the results for ABT-450/r and the potential it holds for treatment-experienced and treatment-naive patients with HCV," said Jay Luly, Ph.D., president and chief executive officer, Enanta Pharmaceuticals.

Study Objectives and Design

The objectives of the 48-week Phase 2 study are to assess the safety, tolerability, pharmacokinetics, and antiviral activity of multiple dose strengths of ABT-450/r in treatment-naive adults infected with HCV genotype 1, which is the most common and difficult to treat form of the infection in the developed world. Trial endpoints include early virologic response and rapid virologic response. Initial antiviral activity was evaluated via a 3-day treatment period during which ABT-450/r was administered alone. Subsequently, ABT-450/r was administered with pegIFN/RBV (SOC) for 12 weeks, followed by treatment with SOC alone for an additional 36 weeks. Participants are then monitored post therapy for 24 weeks for sustained virologic response.

In the trial, the most common adverse events reported in subjects receiving ABT-450/r in combination with pegIFN/RBV were headache, fatigue, insomnia and depression. A similar proportion of subjects reported at least one adverse event in all treatment groups, including placebo.

ABT-450 is being developed with low-dose ritonavir, which enhances the pharmacokinetic properties of ABT-450, allowing for once-daily dosing. The use of ritonavir 100 mg with ABT-450 for the treatment of HCV is investigational.

About the Hepatitis C Virus

Hepatitis C is a liver disease affecting more than 180 million people worldwide. The virus is primarily spread through direct contact with the blood of an infected person. HCV increases a person's risk of developing chronic liver disease, cirrhosis, liver cancer and death.

Liver disease associated with HCV infection is growing rapidly, and current therapies only cure about half of patients with the genotype 1 form of the virus. Specifically targeted antiviral therapies for HCV, such as protease inhibitors and non-nucleoside polymerase inhibitors, may have the potential to increase the proportion of patients in whom the virus can be eradicated.

Ritonavir Use in Treatment of HIV

Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.

Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV

Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death. Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

For more information, please see the Important Safety Information and full Prescribing Information for ritonavir.

About Enanta

Enanta Pharmaceuticals is a research and development company that uses its novel chemistry approach and drug discovery capabilities to create best in class small molecule drugs in the infectious disease field. Enanta is developing novel protease, NS5A, nucleoside(tide) polymerase, and cyclophilin-based inhibitors targeted against the Hepatitis C virus (HCV). Additionally, the Company has created a new class of macrolide antibiotics, called Bicyclolides, which overcomes bacterial resistance. Antibacterial focus areas include superbugs, respiratory tract infections, and intravenous and oral treatments for hospital and community MRSA. Enanta is a privately held company headquartered in Watertown, Mass. Enanta's news releases and other information are available on the company's web site at http://www.enanta.com/.

About Abbott

Abbott's HCV development programs include its partnership with Enanta Pharmaceuticals to discover protease inhibitors, as well as internal programs focused on additional viral targets, including polymerase inhibitors. Abbott currently has four HCV compounds in phase 2 clinical trials, including a protease inhibitor, two polymerase inhibitors and an NS5A inhibitor. Abbott is well positioned to explore combinations of these compounds, a strategy with the potential to markedly transform current treatment practices.

Abbott is a global, broad-based health care company devoted to the discovery, development, manufacturing and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs nearly 90,000 people and markets its products in more than 130 countries.

Abbott's news releases and other information are available on the company's Web site at http://www.abbott.com/.