RxPG News : HCV

Caffeine intake in chronic hepatitis C patients associated with less liver fibrosis

Tue, 05 Jan 2010 13:41:15 PST

( from http://www.rxpgnews.com ) Researchers from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) determined that patients with chronic hepatitis C virus (HCV) who consumed more than 308 mg of caffeine daily had milder liver fibrosis. The daily amount of caffeine intake found to be beneficial is equivalent to 2.25 cups of regular coffee. Other sources of caffeine beyond coffee did not have the same therapeutic effect. Details of this study are available in the January 2010 issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

Liver fibrosis or scaring of the liver is the second stage of liver disease and characterized by a degradation of liver function due to accumulated connective tissue. Past studies have looked at modifiable behaviors, such as coffee consumption, that mitigate the progression of liver disease. A number of studies have looked at the benefits of higher coffee intake with results that include: lower prevalence of chronic liver disease, reduced risk of hepatocellular carcinoma (liver cancer), and lower risk of death from cirrhosis complications. "From data collected to date it remains unclear whether coffee itself, or caffeine provides the beneficial effect," said Apurva Modi, M.D. and lead author of the current study that focuses on caffeine intake and its impact on liver fibrosis.

From January 2006 to November 2008 all patients evaluated in the Liver Disease Branch of the National Institutes of Health were asked to complete a questionnaire to determine caffeine consumption. Questions were asked pertaining to all sources of caffeine including regular and diet soft drinks; regular and decaffeinated coffee; black, green, Chinese and herbal teas; cocoa and hot chocolate; caffeine-fortified drinks; chocolate candy; caffeine pills; and medications with caffeine. Participants were asked about their frequency of caffeine consumption, which was quantified as never; 1-3 times per month; 1, 2-4, or 5-6 times per week; 1, 2-3, 4-5, and 6 or more times per day.

The analysis included 177 participants who were undergoing liver biopsy with a mean age of 51 years and mean body mass index (BMI) of 27.5. Of those in the cohort 56% were male, 59% Caucasian, 19% Black, 19% Asian, 3% Hispanic, and 68% had chronic HCV. Daily consumption of caffeine from food and beverages raged from none to 1028 mg/day with an average of 195 mg/day, which is equivalent to 1.4 cups of coffee daily. Most caffeine consumed came from regular coffee (71%) followed by caffeinated soda (13%), and black tea (4%). Repeated administration of the questionnaire within a 6-month period displayed consistent responses suggesting caffeine intake does not significantly change over time.

Patients with an Ishak fibrosis score of less than 3 had a mean caffeine intake of 212 mg/day compared with 154 mg/day for those with more advanced fibrosis. The Ishak fibrosis score is the preferred system that measures degree of liver scarring with 0 representing no fibrosis through 6 indicating cirrhosis. For each 67 mg increase in caffeine consumption (about one half cup of coffee) there was a 14% decrease in the odds of advanced fibrosis for patients with HCV. "Our data suggest that a beneficial effect requires caffeine consumption above a threshold of approximately 2 coffee-cup equivalents daily," noted Dr. Modi. The protective effects of consuming more than 308 mg of caffeine daily persisted after controlling for age, sex, race, liver disease, BMI and alcohol intake for all study participants.

Researchers further evaluated caffeine and coffee separately to determine the individual effect of each on fibrosis. Results showed that consumption of caffeinated soda, green or black tea was not associated with reduced liver fibrosis. However, a significant protective effect could have been missed due to small numbers, as 71% of total caffeine consumed came from coffee. Caffeinated coffee had the most pronounced effect on reduced liver fibrosis. The authors suggest that further research is needed to determine if the protective benefits of coffee/caffeine intake plateau at amounts beyond the daily consumption threshold.

Bavituximab Shows Promising Anti-Viral Activity in Monotherapy HCV Trial

Thu, 08 Jun 2006 06:17:37 PST

( from http://www.rxpgnews.com ) Peregrine Pharmaceuticals, a biopharmaceutical company developing targeted therapeutics for the treatment of cancer and hepatitis C virus infections, today reported top-line results on the effect of bavituximab (formerly Tarvacin) on viral RNA serum titers when administered as single dose monotherapy in a Phase Ia study in patients with chronic hepatitis C virus (HCV) infection. In this analysis, bavituximab showed signs of anti-viral activity at all four study dose levels, and it also showed evidence of a prolonged anti-viral effect.

These preliminary efficacy data follow positive safety data from the Phase Ia study that Peregrine reported on February 27, 2006, indicating that bavituximab was well tolerated, with no dose limiting toxicities observed. Peregrine also announced today two additional milestones in the bavituximab HCV clinical program. First, the company has completed the treatment phase of an additional, higher dose cohort that was added to the Phase Ia HCV study after the first four cohorts were complete, and second, it has begun dosing patients in a new Phase Ib repeat dose study in HCV patients.

In the Phase Ia study, more than 90% of the subjects were infected with the genotype 1 form of HCV, which is the most common and difficult to treat strain of the virus. All participants had failed or relapsed after receiving standard-of-care treatments. Subjects were administered bavituximab at 0.1, 0.3, 1 or 3 milligram per kilogram (mg/kg) of body weight.

After a single dose of bavituximab, among patients treated with the higher 1mg/kg and 3mg/kg dose levels, 50% achieved a greater than 75% (0.6 log) reduction in serum HCV RNA with a maximum 97% (1.5 log) reduction. These patients had an average reduction in serum HCV RNA levels of 0.8 log during the course of the 12-week follow-up period. Signs of anti-viral activity were seen at all dose levels including the initial dose of 0.1mg/kg. Even at this low dose, one-third of patients experienced a greater than 75% (0.6 log) reduction in serum HCV RNA levels.

Bavituximab also showed signs of durable anti-viral activity after a single dose, with some subjects achieving a greater than 80% (0.7 log) reduction in viral load by day four and maintaining a greater than 60% reduction in serum HCV levels up through the end of the study at week 12.

"This preliminary evidence of anti-viral activity in this first-in-human single dose study of bavituximab is very encouraging," said Dr. Eliot W. Godofsky, principal investigator of the Phase Ia study, and director of the University Hepatitis Center in Sarasota Florida. "Bavituximab is a potentially novel approach to treating chronic hepatitis C infection, one with a unique mechanism of action that should complement both existing and investigational therapies in development. Based on its safety profile to date and these promising signs of anti-viral activity, we look forward to working with Peregrine to assess bavituximab in the repeat dose trial, as well as its potential for use in combination regimens to control and ultimately eradicate HCV."

These initial efficacy findings for a single dose of bavituximab are noteworthy for several reasons. First, the rapid virus production and turnover characterizing HCV infection typically limit the impact of a single dose of any anti-viral drug. Second, preclinical data supports that bavituximab's unique mechanism of action, which mobilizes the body's immune system to attack the hepatitis C virus, is likely to be most effective when administered as part of a multiple dose regimen. Third, most other investigational drugs for HCV infection have reported initial efficacy results following multiple dose or combination regimens that include standard-of-care therapies. In this study bavituximab was administered as monotherapy to patients who had failed standard treatment. In view of these factors, the anti-viral activity demonstrated in this single dose, monotherapy study is all the more encouraging.

"We are delighted with these first positive indicators of bavituximab's anti-viral potential in HCV patients," said Steven W. King, president and CEO of Peregrine. "The initial human results for this first-in-class novel agent are very promising. Its excellent overall safety profile to date, early evidence of anti-viral activity and signs of prolonged duration of activity give additional impetus to our efforts to advance bavituximab as a potential new therapy for the treatment of HCV and other serous viral infections."

Joseph Shan, Peregrine's executive director of clinical and regulatory affairs, added, "These first efficacy results in humans are particularly exciting because researchers did not expect to see much anti-viral activity after a single dose of drug, based on our experience in lethal animal disease models such as Lassa fever. Bavituximab demonstrated good anti-viral activity in these studies, but only after administration of multiple doses. Based on the results reported today, the drug's anti-viral potential may be even more promising in humans than the animal models suggest."

Patients in the fifth dosing cohort (6mg/kg) of the Phase Ia HCV study are currently in the 12-week follow-up period, and data from this group will be available later this year. The repeat dose Phase Ib HCV study that is underway is designed to evaluate multiple doses of bavituximab for safety as well as assessing changes in serum HCV RNA levels. Enrollment in this study is expected to be completed by the end of the year.

Treating obesity improves efficacy of hepatitis C therapy

Sat, 03 Jun 2006 09:43:37 PST

( from http://www.rxpgnews.com ) According to a new study, obese patients chronically infected with the hepatitis C virus (HCV) and treated with combination drug therapy may have better outcomes if the underlying abnormalities caused by excessive fat tissue are corrected. Weight loss, medications to decrease insulin resistance and extending duration or dosage of therapy are strategies that may improve the efficacy of therapy.

HCV is one of the leading causes of chronic liver disease worldwide, affecting 3 percent of the world's population. In the U.S. alone 4.1 million people have been infected with HCV, and up to 85 percent of those are chronic carriers of the virus. Up to 70 percent of chronic carriers will go on to develop some other form of chronic liver disease, from mild liver enzyme abnormalities to cirrhosis and liver cancer. While there is no vaccine for HCV, the current optimal treatment is combination therapy with peginterferon alfa (an immune stimulant) and ribavirin (an inhibitor of viral replication). However, this will cure only 55 percent of patients. One of the risk factors for treatment failure is obesity.

Obesity itself is linked to the disruption of hormone signaling pathways that affect cell function and to abnormal levels of circulating proteins and sugars. In other words, obesity is associated with a wide range of metabolic changes that affect multiple cellular and organ functions. This biochemical disregulation is linked to serious chronic medical conditions, such as heart disease, diabetes, and non-alcoholic fatty liver disease.

Given the association between obesity and metabolic abnormalities, Michael R. Charlton, M.D. of the Division of Gastroenterology and Hepatology at the Mayo Clinic and Foundation in Rochester, MN and coauthors reviewed several mechanisms by which obesity may interfere with the treatment of chronic HCV and recommend management strategies for obese patients.

The authors identify three possible ways by which obesity may interfere with peginterferon alpha and ribavirin activity. First, fat tissue actively secretes hormones that can modulate the immune system. Increases in fat tissue may disregulate immune pathways peginterferon targets, rendering the drug ineffective. Second, obesity causes insulin resistance which itself leads to the accumulation of fat in the liver. The greater the accumulation of fat in the liver, the greater the risk of fibrosis, or scar tissue formation, that alters liver function and blood flow, often permanently. Because HCV also causes liver cells to not respond to insulin, obesity may simply compound the problem and worsen liver disease. Third, fat tissue reduces the amount of peginterferon circulating in the body. The decreased circulation of the drug may also weaken peginterferon's stimulation of the immune system against HCV.

To address all of these mechanisms, the authors make three treatment recommendations. First, weight loss to reduce fat tissue would address all three hypothesized mechanisms. Weight loss in obese HCV patients is already associated with improved liver biopsy results and liver enzyme levels. Second, treatment with drugs that improve cellular sensitivity to insulin, such as the diabetes drugs metformin or pioglitazone, would lead to reduced fat accumulation in liver cells and might reverse disease progression. Third, increasing the dosages or the duration of combination therapy may increase circulating drug levels and improve drug efficacy.

"Treatment strategies that focus on improving underlying metabolic factors associated with poor response to combination therapy are thus more likely to overcome the low sustained viral response rates often observed in obese patients infected with HCV," conclude the authors.

Molecular mechanism that inhibits HCV replication discovered - Tang-Nelson study

Wed, 08 Feb 2006 11:37:37 PST

( from http://www.rxpgnews.com ) The hepatitis C virus (HCV) infects more than 170 million people worldwide and leads to both acute and chronic liver diseases. Since its discovery several decades ago, the insidious human pathogen has stymied the quest for anti-viral therapies by refusing to reproduce in test tubes for more than a few hours or days, denying scientists an efficient virus production and infection system for experimental research.

Now, in a landmark study by Florida State University biologists that could bolster the development of anti-viral therapies for HCV as well as for related RNA viruses such as West Nile and influenza Assistant Professor Hengli Tang and doctoral student/co-author Heather B. Nelson have discovered the molecular mechanism that inhibits HCV replication in vitro after its host cells become crowded and stopped dividing.

What's more, their groundbreaking discovery came about as a result of the new test they developed that can quickly and easily monitor HCV replication in the laboratory.

Finally, after Tang and Nelson uncovered the reason for suppression of the virus in cell culture in a nutshell: not enough nucleotide molecules, the building blocks of HCV they then adapted an existing cell technology to remedy the problem right in the test tube.

"Our findings could prove critical to research on HCV's complex virus-host cell interactions and lead to better, targeted treatments," Tang said.

"Currently, any nucleotide starvation therapies, used primarily to treat cancer, can inhibit replication by depriving viral agents of their molecular building blocks. However, those therapies may impact healthy cells, as well, causing undesired side effects."

In the human liver, the parasitic HCV makes copies of its genetic material by hijacking nucleotides the little molecules produced by its dividing host cells. It is only in the liver that pools of nucleotides remain available to HCV in sufficient supply after the host cells reached confluence (stop dividing).

Not so in test tubes, say the FSU researchers.

To address the shortage of HCV building blocks in vitro, their unique adaptation of an existing cell technology enabled the introduction of nucleoside molecules to a culture of liver cancer cells. The nucleosides then converted to the essential nucleotide molecules that Tang calls the missing link. In turn, the nucleotides generated in vitro replication of infectious HCV particles that continued even after host cell confluence as it does in the liver.

That's not all. "Our new cell line also allows us to rapidly identify and isolate drug-resistant HCV mutants in vitro and to screen for anti-viral drug candidates," Tang said. "This will help researchers better study the mechanism of drug resistance, a big problem with this virus and others such as HIV (human immunodeficiency virus) that mutate quickly."

Underpinning everything, Tang says, is their novel, easy-to-use assay. It can track mutant strains of HCV in a week or less while other assays take weeks or months.

"Our assay, for which FSU has filed a provisional patent application, employs a new reporter cell line, which means the cells give out a detectable signal when certain events happen inside them," said Tang. "In this case, they emit a green fluorescence whenever HVC is replicating. The fluorescence is tracked in the cell culture through a technique known as flow cytometry, which employs a machine equipped with a laser and lights that follows the green to find the virus."

Between earning his Ph.D. at the University of California-San Diego in 1998 and joining FSU's biological science faculty in 2004, Tang served as a lead researcher in an industry setting, seeking targeted anti-viral therapies primarily for HIV.

"I find it particularly rewarding to play a part in research that may actually help somebody soon," he said.

Extrahepatic sites may cause rapid recurrence of Hepatitis C after liver transplantation

Fri, 03 Feb 2006 16:02:37 PST

( from http://www.rxpgnews.com ) When a diseased liver is removed from a patient with Hepatitis C (HCV), serum viral levels plummet. However, after receiving a healthy liver transplant, virus levels rebound and can surpass pre-transplant levels within a few days, according to a new study published in the February 2006 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS).

Hepatitis C is the number one reason for liver transplantation, however, the virus always recurs in the new liver. Since mathematical models have been useful in the study of the viral dynamics of HIV and hepatitis B, researchers, led by Kimberly A. Powers and Ruy M. Ribeiro of the Los Alamos National Laboratory in New Mexico, sought to use a mathematical model to quantify the liver reinfection dynamics of HCV.

The researchers, in collaboration with a surgical team lead by John McHutchison now at Duke University Medical Center, followed six HCV-infected patients who received cadaveric liver transplants. They collected blood samples before, during and after transplantation to assess changing levels of HCV RNA which was measured using reverse transcription polymerase chain reaction assay. They then plugged the data into a mathematical model, correcting for fluid balance, and analyzed the results using linear regression.

"In most patients," the authors report, "HCV RNA levels decreased rapidly during and after transplantation and subsequently began to increase reaching above pre-transplant levels in all but one patient within a few days of the procedure." They found that when the diseased liver was removed, virus levels dropped with an average half-life of 48 minutes. After the new liver was implanted, they found that virus levels continued to drop for up to 23 hours, then began to rise, doubling every 2 days.

Notably, in three patients, the virus levels plateaued before rising, suggesting, say the authors "that a non-hepatic source supplied virions and balanced their intrinsic clearance." The authors estimate, however, that non-hepatic sources can only account for 4 percent of total viral production. Ninety-six percent of it occurs in the liver.

The patterns of viremia decline and increase seen in this study are consistent with previous studies, although this study indicates a much faster virion half-life than previously suggested. The findings also support the notion that HCV can replicate rapidly in the post-transplant immunosuppressed patient, leading the authors to suggest that early antiviral therapy may delay or prevent reinfection.

The study was limited by the small number of patients and the single compartment model, which did not separately account for liver and extrahepatic sites of viral replication. "Nevertheless," report the authors, "the rapid HCV RNA decline in the anhepatic phase, followed by the postoperative increase observed in several patientssuggest that the liver is the primary site of viral replication, with at most small contributions from extrahepatic sites."

In conclusion, the authors write, "Continued work towards elucidating extrahepatic replication, the time-course of reinfection, the effects of immunosuppressive therapy, and the relationships among viremia, infection and liver damage will be beneficial in optimizing treatment for HCV patients undergoing liver transplantation."

How Hepatitis C virus highjack protein synthesis machinery in humans

Sun, 04 Dec 2005 10:10:38 PST

( from http://www.rxpgnews.com ) Scientists have uncovered key new information towards understanding the crucial first step in protein synthesis, the process by which the genetic code, harbored within DNA and copied into RNA, is translated into the production of proteins. This new information also helps to explain how viruses, such as Hepatitis C, are able to highjack protein synthesis machinery in humans for their own purposes.

Biochemist Jennifer Doudna and biophysicist Eva Nogales, both of whom hold joint appointments with the Lawrence Berkeley National Laboratory (Berkeley Lab), the University of California at Berkeley, and the Howard Hughes Medical Institute (HHMI), led a study in which cryo electron microscopy (cryo-EM) was used to create a 3-D model of the protein complex called eukaryotic translation initiation factor 3 (eIF3). The model showed that the eIF3 protein complex employs the same structural mechanics in the loading of either human or viral RNA to ribosomes, the complex machinery in living cells responsible for protein synthesis.

This is the first insight into how the initiation mechanisms of protein synthesis work specifically for humans, and a step towards understanding at the molecular level what happens when a viral infection occurs, said Doudna, a member of Berkeley Labs Physical Biosciences Division. A better understanding of these mechanisms could open the door to new and improved therapies for viral infections.

Said Nogales, also a member of Berkeley Labs Physical Biosciences Division, Using cryo-EM, we can reconstruct images of the entire protein ensemble to study the molecular machinery behind the protein synthesis process. We now have the tools to see how the many different parts of the molecular machinery come together.

The results of this study are in the December 2, 2005 issue of the journal Science, in a paper entitled
Structural Roles for Human Translation Factor eIF3 in Initiation of Protein Synthesis. Co-authoring the paper with Doudna and Nogales were Bunpote Siridechadilok and Christopher Fraser of UC Berkeley, and Richard Hall of Berkeley Lab.

Proteins, the curiously-shaped macromolecules that serve as the basic construction material of all living cells, and also initiate and control nearly all cell chemistry, are assembled out of amino acids according to the instructions contained within the genes. These genetic instructions are carried from the DNA inside a cells nucleus out into the cells cytoplasm via messenger RNA (mRNA). There the information will be translated to a sequence of amino acids via the ribosome, an ancient organelle so highly conserved by evolution that its core components are pretty much the same for all forms of life.

Protein synthesis in mammalian cells begins with the loading of mRNA onto the small ribosome subunit, 40S, which is, in part, one of the responsibilities of the eIF3 complex. The eIF3 complex also interacts with other translation elements that bind at the start of the mRNA, prevents premature joining of the 40S and 60S ribosomal subunits, and helps assemble active ribosomes. Until now, the structural basis for eIF3s multiple activities has been unknown.

At a resolution of 30 angstroms, the cryo-EM reconstructions of Doudna and Nogales and their collaborators show eIF3 to be a particle consisting of five lobes - analogous to a head, and a pair of arms and legs. The study shows that the left arm of the eIF3 complex binds to the eukaryotic protein complex that recognizes the methylated guanosine cap at the 5-end of the eukaryotic mRNAs (mRNA consists of a coding region sandwiched between a 5-end and a 3-end). By drawing the mRNAs 5-end cap through the ribosome entry site and towards the exit, eIF3 ensures the mRNA is properly positioned for its genetic code to be translated.

Acting like a molecular wrestler, eIF3 will also wrap its arms and legs around a structural element of RNA for the hepatitis C virus (HVC), known as the internal ribosome entry site (IRES), and pin it to the exit site of the 40S ribosome subunit. The IRES leaves through the left arm of the eIF3 complex at the same location where interaction with the human mRNA cap-binding complex takes place.

This might explain the amazing ability of the HVC IRES to hijack the human ribosome and its associated translation factors, said Doudna.

Said Nogales, The position of eIF3 in our models also provides a plausible explanation for its role in preventing premature joining of the 40S and 60S ribosome subunits.

Breastfeeding does not raise risk of HCV transmission

Tue, 01 Nov 2005 12:52:38 PST

( from http://www.rxpgnews.com ) Breastfeeding does not raise the risk of mother-to-child transmission of hepatitis C virus (HCV), according to two new studies published in the December 1 issue of The Journal of Infectious Diseases, now available online.

One study found that infant girls are twice as likely to be infected as infant boys. Both studies provide new information with which to counsel pregnant women infected with HCV. Taken together, the two new studies expand upon preliminary data from smaller studies of mother-to-child transmission of HCV.

The larger of the two studies, conducted by the European Paediatric Hepatitis C Virus Network, involved 1,479 mother-and-child pairs enrolled at 33 centers in Italy, Spain, Germany, Ireland, the United Kingdom, Norway, and Sweden. The other study, by Eric E. Mast, MD, MPH, of the U.S. Centers for Disease Control and Prevention and colleagues, followed 244 infants born to infected mothers in Houston and Honolulu.

The finding of gender differences in HCV infection was reported by the European authors, who hypothesized that their result may reflect hormonal or genetic differences between men and women in susceptibility or response to infection. Other risk factors significantly associated with transmission were the time in labor (a risk factor in both studies) and use of internal fetal monitoring devices (a risk factor in the U.S. study only).

Although breastfeeding is a known risk for HIV transmission, both studies found it was not associated with transmission of HCV. The European study also found that caesarean section delivery, infant prematurity, and maternal history of injection drug use were not associated with HCV transmission.

The overall rate of transmission of the virus from infected mother to child was 6.2 percent in the European study and 3.6 percent in the U.S. study.

"Our results strongly suggest that women should not be offered an elective caesarean section or discouraged from breastfeeding on the basis of hepatitis C infection alone," said Pier-Angelo Tovo, MD, the lead author of the European study.

"Our findings support existing recommendations to avoid internal fetal monitoring and prolonged laborin infected women," wrote the U.S. authors.

In an accompanying editorial, R. Palmer Beasley, MD, of the University of Texas at Houston, emphasized the European study's novel finding of a gender difference in transmission rates and suggested that higher HCV rates in female newborns may be due to excess mortality in infected males in utero. "Overall, the observation of higher hepatitis C virus infection rates in female infants is in accord with recent observations of similar excesses in HIV infection of female infants," Dr. Beasley said.

Celgosivir Cleared for Phase IIb Combination Study in HCV Non-responders

Thu, 11 Aug 2005 23:18:38 PST

( from http://www.rxpgnews.com ) MIGENIX Inc. , a clinical-stage developer of drugs for infectious and degenerative diseases, has received a Notice of Authorization from Health Canada for a clinical trial application (CTA) to begin a Phase IIb combination study of MX-3253 (celgosivir), a compound in development for the treatment of chronic hepatitis C virus (HCV) infections. Enrollment in the study is expected to commence in the next few weeks with results expected around mid- year calendar 2006.

"This is an important step in the development of celgosivir", stated Jim DeMesa, MD, President and CEO of MIGENIX. "Our recent agreement with Schering- Plough, the strong preclinical synergy of celgosivir with interferon-alpha plus ribavirin, and the participation of many of the same investigators from our Phase IIa trial - combined with this regulatory approval - give us great encouragement for success in this Phase IIb trial".

About MX-3253 and the Phase IIb Combination Study

MX-3253 (celgosivir) is an alpha-glucosidase I inhibitor and is currently the only oral anti-HCV drug in development that acts through host-directed glycosylation. In preclinical studies, celgosivir has demonstrated strong synergy with interferon-alpha plus ribavirin and has the potential to be included as part of a combination therapeutic approach to improve efficacy. Celgosivir is currently being evaluated in a Phase IIa monotherapy study in treatment-naive and interferon-intolerant genotype I HCV patients with results of the study expected before the end of the third quarter of calendar 2005.

The Phase IIb combination study of MX-3253 is a randomized, multi-center, active-controlled, 12 week evaluation of MX-3253 in three treatment arms of up to 20 chronic HCV patients each: celgosivir plus peginterferon alfa-2b plus ribavirin (3-way combination); celgosivir plus peginterferon alfa-2b (2-way combination); and placebo plus peginterferon alfa-2b plus ribavirin (control). An agreement was completed in July with Schering-Plough for (a) the supply of PEGETRON(TM) (peginterferon alfa-2b powder for solution plus ribavirin 200 mg capsules) and (b) certain technical and laboratory support and other services for the study.

Patients for the Phase IIb study will be selected based on having genotype 1 chronic HCV and having failed to respond to pegylated alpha interferon plus ribavirin therapy (non-responders). Today, there are very limited treatment options for the 40% to 50% of hepatitis C patients who have failed treatment with the current standard of care, pegylated interferon plus ribavirin. Among this patient population, approximately 10% respond to retreatment with pegylated interferon plus ribavirin. Patients who respond to therapy during the Phase IIb trial will have the option to continue on treatment for up to 48 weeks. The study will measure viral load at various time points, as well as a number of safety parameters.

Albuferon in Phase 2b Trial for the Treatment of Chronic Hepatitis C

Thu, 02 Jun 2005 13:15:38 PST

( from http://www.rxpgnews.com ) Human Genome Sciences, Inc. announced today that it has begun dosing patients in a Phase 2b clinical trial of Albuferon(TM) (albumin-interferon alpha) in combination with ribavirin to evaluate the efficacy and safety of Albuferon in patients with chronic hepatitis C virus (HCV) genotype 1 who are naive to interferon alpha-based treatment regimens. Genotype 1 accounts for nearly 70% of all HCV infections in North America and is generally regarded as the most difficult HCV genotype to treat.(1)

The trial is a randomized, open-label, multi-center, active-controlled, dose-ranging study conducted in Australia, Canada, Czech Republic, France, Germany, Israel, Poland and Romania. A minimum of 440 patients will be enrolled in the Phase 2b study and randomized into four treatment groups, three of which will receive subcutaneously administered Albuferon (900 mcg at 14-day intervals, 1200 mcg at 14-day intervals, and 1200 mcg at 28-day intervals(1)). The fourth treatment group will serve as the active control group and will receive weekly 180-mcg doses of subcutaneously administered Pegasys (peginterferon alfa-2a). All patients will receive weight-based oral daily ribavirin at 1000 or 1200 mg in two divided doses. The primary objectives of the Phase 2b study are to evaluate the efficacy and safety of Albuferon in combination with ribavirin in interferon alpha-naive patients with chronic hepatitis C genotype 1. The primary efficacy endpoint will be sustained virologic response, defined as undetectable virus at 24 weeks after completion of 48 weeks of treatment.

John McHutchison, M.D., Coordinating Center Principal Investigator for the Phase 2b study, and Professor of Medicine and Director, GI/Hepatology Research, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, said, "The current standard of care for the treatment of chronic hepatitis C is a combination of pegylated interferon alpha and ribavirin. This combination produces cures in approximately 42-46 percent of all genotype 1 HCV patients completing therapy, leaving more than 50 percent who relapse or do not respond. Clearly, chronic hepatitis C represents a significant unmet medical need. The preclinical and clinical evidence to date supports the continued evaluation of the potential of Albuferon to help meet this need. The next logical step is the current study of Albuferon in combination with ribavirin in a larger population of treatment-naÃ¯ve genotype 1 patients with chronic hepatitis C."(2-11)

David C. Stump, M.D., Executive Vice President, Drug Development, said, "Based on the preclinical and clinical results that have emerged thus far, we believe that Albuferon has the potential to become an important therapeutic option for the treatment of chronic hepatitis C. The Phase 2b study announced today is the largest Albuferon trial to date. We recently reported the positive results of a Phase 2 study of Albuferon monotherapy in interferon alpha-naÃ¯ve patients with genotype 1 hepatitis C.(12-13) The data that emerged demonstrate that Albuferon is well tolerated, has a prolonged half- life and shows robust antiviral activity, with durable dose-dependent reductions in HCV viral load. The data also enabled our identification of the range of active doses that will be evaluated in the larger Phase 2b trial announced today. In February 2005, we disclosed preliminary data from a separate ongoing Phase 2 clinical trial of Albuferon in combination with ribavirin, which show that Albuferon can be administered safely and repetitively at 2-week or 4-week intervals in combination with ribavirin in patients who have failed to respond to previous interferon alpha-based treatment regimens.(14) The results of clinical and preclinical studies to date afford confidence in the ability to administer Albuferon safely in combination with ribavirin to treatment-naÃ¯ve patients.(15-21) We are hopeful that Albuferon will one day provide an important therapeutic option for the treatment of chronic hepatitis C."

The results of a Phase 2 clinical trial of Albuferon monotherapy in interferon alpha-naive patients with genotype 1 chronic hepatitis C were presented at the 40th Annual Meeting of the European Association for the Study of the Liver (EASL).(12-13)

Data presented on 56 patients demonstrate that Albuferon exhibited robust antiviral activity in genotype 1 HCV. A mean reduction in HCV viral load of 3.2 log at Day 28 was observed in the combined 900 mcg and 1200 mcg dose cohorts, with 69% of patients (18/26) in these cohorts showing a more than 2-log reduction in HCV viral load at Day 28. Undetectable viral load was observed at Day 42 (28 days after the second injection) in 23% of patients (6/26) in the combined 900 mcg and 1200 mcg dose cohorts.

Robust dose-dependent viral kinetics were observed, with the majority of patients in the 900 mcg and 1200 mcg cohorts exhibiting a second-phase decline in viral load of more than 0.3 log per week, which has previously been shown to be predictive of sustained virologic response (SVR) in treatment with the pegylated interferons.(22)

Reductions in viral load of equal to or greater than 2 log are reported in approximately 42% of genotype 1 HCV patients treated with pegylated interferon alpha products in combination with ribavirin.(23) The results presented at EASL demonstrate that Albuferon remained in the blood substantially longer than is reported for recombinant interferon alpha and pegylated interferon alpha. Albuferon exhibited a median half-life of 148 hours, supporting dosing at intervals of 2-4 weeks. This compares with a reported mean (range) elimination half-life of 80 hours (50-140 hours) for Pegasys and 40 hours (22-60 hours) for PEG-Intron.(23-25) Albuferon was well tolerated with adverse events that were transient and mostly mild to moderate in severity. There were no discontinuations due to reductions in hematologic cell counts. No subjects developed newly emergent antibodies to alpha interferon.

Albuferon is a novel, long-acting form of interferon alpha. Recombinant interferon alpha is approved for the treatment of hepatitis C, hepatitis B and a broad range of cancers. Human Genome Sciences modified interferon alpha to improve its pharmacological properties by using the company's proprietary albumin fusion technology.

Hepatitis C infection is an inflammation of the liver caused by the hepatitis C virus. It is the most common chronic blood-borne infection in the developed world. It is estimated that as many as 170 million people worldwide are infected with hepatitis C virus. This includes nearly four million people in the United States. The hepatitis C virus is transmitted primarily through significant or repeated exposures to infected blood. Intravenous drug use and sexual contact with infected persons account for the majority of new hepatitis C infections. When detectable levels of the hepatitis C virus in the blood persist for at least six months, a person is diagnosed as having chronic hepatitis C.

Valopicitabine Shows Potential Therapeutic Response in the Treatment of Genotype 1 Hepatitis C Patients

Thu, 14 Apr 2005 20:32:38 PST

( from http://www.rxpgnews.com ) Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX - News), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases, today announced preliminary phase IIa clinical trial data for valopicitabine (NM283) in treatment naive genotype 1 hepatitis C patients.

In this phase IIa clinical trial, 9 patients receiving the combination of valopicitabine and pegylated interferon have reached 24 weeks of treatment, and achieved a mean reduction in serum HCV RNA of 4.5 log10, or more than 99.99 percent. These data will be presented at the 40th Annual Meeting of the European Association for the Study of the Liver (EASL) in Paris, France on Sunday, April 17 at 12:00 p.m. Central European Time (CET) by Nezam Afdhal, M.D., of Harvard Medical School.

In January, Idenix reported 12-week data on 12 patients receiving valopicitabine plus pegylated interferon combination therapy. Of the 12 patients previously reported, nine patients have now reached 24 weeks of combination treatment and have experienced substantial additional antiviral response. In eight out of the nine patients, levels of virus have decreased to below 600 IU/mL, which is the lower quantification limit of the Amplicor(TM) PCR assay, an assay typically used by physicians to monitor the effectiveness of hepatitis C treatment. Six of the nine patients achieved undetectable levels of virus utilizing the real-time TaqMan® PCR assay, an assay with a high level of sensitivity, which has a detection limit of 10 IU/mL.

"This is the first time that we are seeing 24-week data for an antiviral drug directly targeting a specific enzyme of the hepatitis C virus," said Nezam Afdhal, M.D., a principal investigator in the phase IIa valopicitabine trials and Chief of Hepatology at Beth Israel Deaconess Medical Center in Boston and Associate Professor at Harvard Medical School. "These preliminary data are promising and suggest that direct antiviral drugs, such as valopicitabine, could set a new treatment standard in hepatitis C, by offering hepatitis C patients, particularly patients infected with HCV genotype 1, potentially improved clinical benefit with fewer side effects."

Clinical Trial Design: A total of 30 patients in the phase IIa clinical trial were enrolled and randomized to one of two treatment arms so that 18 patients receive the combination of valopicitabine and pegylated interferon and 12 patients receive valopicitabine monotherapy. Patients on combination treatment receive a titrating dose of valopicitabine once a day up to 800 mg by day 8 and then continue this dose throughout the treatment period. Additionally, a Peg-Intron® dose of 1.0 mcg/kg is administered once a week starting on day 8. Enrolled patients are treatment naive, HCV genotype 1, with baseline viral load greater than 5 log10 IU/mL and alanine aminotransferase (ALT) levels less than 5 times the upper limit of normal. With the agreement of the clinical trial investigators and submission of protocol amendments to the United States Food and Drug Administration (FDA), Idenix has extended the treatment duration of this clinical trial from the initially planned 28 days, to 12 weeks, then 24 weeks and finally to 48 weeks based on the interim results.

Clinical Trial Results: Of the 30 patients enrolled, one has recently begun treatment, 25 have reached 12 weeks of treatment and four patients discontinued treatment prior to week 12. Two of these withdrawals were interferon-related, one patient consented only to participate in the initial 28-day clinical trial and one was lost to follow-up. Results for the group that have reached 12 weeks of treatment are consistent with the previously announced 12-week findings reported in a company press release on January 10, 2005. The updated 12-week data demonstrate a mean HCV RNA reduction from baseline of 3.01 log10 IU/mL, or 99.9 percent, for the 16 patients in the combination treatment group, and 0.87 log10 IU/mL, or 86.5 percent, for the 12 patients in the valopicitabine monotherapy group.

To date, 10 patients have reached 24 weeks of treatment. Nine patients in the valopicitabine plus pegylated interferon treatment group have completed 24 weeks of treatment. The mean HCV RNA reduction from baseline for those patients was 4.5 log10 IU/mL, or more than 99.99 percent. One patient in the monotherapy group continued treatment after week 12, and after 24 weeks of treatment experienced an HCV RNA reduction from baseline of 1.9 log10 IU/mL. Six of the nine patients receiving the combination treatment achieved virus levels below the level of detection by real-time PCR, an assay with a high level of sensitivity (<10 iu ml/