Entry inhibitors show promise as drugs with new MOA for treatment of HBV and HDV infection


Promising new viral hepatitis data presented today at the International Liver CongressTM show that entry inhibitors --a new mechanism of action for drugs to treat viral hepatitis -- could provide the first new hepatitis B and hepatitis D treatments for many years.^1,2

Most current approved therapies directly target viral replication (e.g. nucleotide/side analogues), and can lead to the development of viral resistance or viral rebound after the end of treatment. Entry inhibitors prevent the virus from entering the cell and forming a stable replication complex, limiting the issue of viral rebound and resistance development.

Professor Heiner Wedemeyer, EASL's Secretary General, commented: "The current treatments available for hepatitis B & D are limited. These novel drugs are the first promising treatments for many years. The shift in the mechanism of action of these drugs from inhibiting the virus's replication directly to inhibiting its entry into the cell, and thus its replication – means they are less likely to produce viral resistance; a huge problem faced by many of today's clinicians."

One study1 showed that treatment of ex-vivo liver cells with synthetic anti-lipopolysaccharide peptides (SALPs) during and prior to HBV infection was highly effective and dose dependent in inhibiting infection – reducing markers of HBV infection (e.g. HBV RNA, HBV antigens) in the concentration range of 4-5 µg/mL by 90% and 0.5-2 µg/mL by 50%.

The study also demonstrated that SALPs showed activity against other viral (e.g. HIV, herpes) and microbial (e.g. peritonitis, colitis and pneumonia) infections. Therefore, SALPs represent a very promising therapeutic strategy to treat viralhepatitis infection and concomitant bacterial infection – which often leads to life threatening systematic complications.

Other studies^2,3 illustrated the enormous value of the chimaeric mouse model of chronic HBV and HDV infection for the preclinical evaluation of antiviral drugs. The study demonstrated that the HBV entry inhibitor Myrcludex-B was able to completely block the spread of HBV from cell to cell and to prevent de-novo HDV infection of human hepatocytes.

Professor Wedemeyer commented: "Although there are 35 million people around the world with HDV infection there is currently little to offer them therapeutically. I am therefore delighted to see these new drug developments."

More information: References

1. Lucifora J et al. Novel peptide-based microbiocides inhibiting hepatitis b virus entry by preventing virus interaction with the cell surface. Abstract presented at The International Liver CongressTM 2011. http://www1.easl.e … rals/338.htm

2. Lutgehetmann M et al. Block of hepatitis delta infection by the entry inhibitor myrcludex b in upa mice: establishment of an efficient mouse model for human HBV/HDV infection. Abstract presented at The International Liver CongressTM 2011. http://www1.easl.e … rals/390.htm

3. Ben M et al. Administration of the entry inhibitor Myrcludex-B after establishment of Hepatitis B Virus infection prevents viral spreading among human hepatocytes in uPA mice. Abstract presented at The International Liver CongressTM 2011.http://www1.easl.e … rals/337.htm

Provided by European Association for the Study of the Liver

New data show non-alcoholic fatty liver disease will reach epidemic status in the US


According to new data presented today at the International Liver Congress, the United States (U.S.) could soon be faced with an epidemic of Non-Alcoholic Fatty Liver Disease (NAFLD)¹, one of the major contributing factors of chronic liver disease (CLD), considered as one of the major causes of morbidity and mortality worldwide. The study highlights that if the current rates of obesity and diabetes continue for another two decades, the prevalence of NAFLD in the US is expected to increase by 50% in 2030.

The study analysed pre-existing clinical survey data over a 10 year period (1988-1994, 1999-2004 and 2005-2008), which included 39,500 adults from three survey cycles. Over the three cycles the prevalence of NAFLD doubled from 5.51% to 11.0% respectively. Furthermore, during the first survey cycle (1988-1994) 46.8% of all CLD's was related to NAFLD but by 2005-2008 this had increased to 75.1%. In addition, the prevalence of obesity and diabetes, the two key risk factors for NAFLD also steadily increased.

Mark Thursz EASL's Vice Secretary commented: "Non-alcoholic fatty liver disease is fast becoming one of the top concerns for clinicians due to the obesity epidemic and it's potential to progress to advanced liver disease which significantly impacts on overall liver-related mortality. This data highlights a serious concern for the future, and the enormous increasing health burden of NAFLD. If the obesity epidemic is anything to go by, the U.S. NAFLD epidemic may have a ripple effect worldwide. It is imperative that health systems continue to drive effective educational programmes to reinforce awareness among the general public to alert them of the risks of obesity and promote the importance of diet and exercise".

NAFLD is the term used to describe fat build-up in liver cells in people who do not drink alcohol excessively and is the most common persistent liver disorder in Western countries with an estimated overall prevalence of 20-30%.²

NAFLD encompasses a spectrum of liver disease associated with insulin resistance, diabetes and obesity and as such people most at risk of NAFLD are those who are obese, have insulin resistance associated with diabetes, high blood pressure and cholesterol.³

More information: References

1. Younossi Z et al., The Changing Face of Chronic Liver Disease (CLD) in the United States: The Rising Epidemic of Non-Alcoholic Fatty Liver Disease (NAFLD). Presented at The International Liver Congress 2011.http://www1.easl.e … rals/204.htm

2. Understanding and Preventing the Progression of Liver Disease in Non-Alcoholic Fatty Liver Disease (NAFLD). Fatty Liver Inhibition of Progression (FLIP)http://www.flip-fp7.eu/ . Accessed March 2011.

3. Fatty Liver. Patient UK. Available at http://www.patient … (Fatty-Liver).htm . Accessed March 2011.

Provided by European Association for the Study of the Liver

PegIFN-lambda shows superior virological response and improved safety than PegIFN-alpha-2a


Highly exciting new data presented today at the International Liver CongressTM found Pegylated Interferon-lambda (PegIFN-lambda) shows superior virological response in HCV patients of genotypes 1-4, with improved safety and tolerability, compared to Pegylated Interferon-alpha (PegIFN-alpha-2a), the current standard of care in chronic HCV.¹

The study results are so important because they show PegIFN-lambda could provide relief for the 20% of HCV patients who have to undergo dose reduction, or cease treatment, on PegIFN-alpha-2a – a part of the current HCV standard of care.²

The trial shows that PegIFN-lambda provides higher rapid virological response (RVR) and complete early virological response (cEVR) than PegIFN-alpha-2a, even in patients with an unfavourable IL28B genotype – which predisposes patients to be resistant to treatment.

Both RVR and cEVR are important markers of a drug's ability to combat HCV infection: RVR is measured as undetectable HCV RNA at week 4 of therapy, maintained up to end of treatment; cEVR is detectable HCV RNA at week 4, but undetectable at week 12, maintained up to end of treatment.

Results at week 12 of the trial show that those HCV genotype 1 and 4 patients given 180µg of PegIFN-lambda achieved RVR 14.7% of the time and cEVR 55.9% of time, compared to 5.8% RVR and 37.9% cEVR in patients given the same dose of PegIFN-alpha-2a.

The study also found PegIFN-lambda was associated with fewer hematologic (blood cell) toxicities, flu-like symptoms, musculoskeletal symptoms, dose reductions and premature discontinuations than the same dose of PegIFN-alpha-2a. However, in the higher dose groups elevations of ALT and bilirubin were observed which may represent drug related toxicity.

Professor Heiner Wedemeyer, EASL's Secretary General, commented: "These are clearly very early results but the combination of better virological response and fewer side effects makes these very exciting findings. The percentage of current HCV patients that have to cease treatment, or have their dose lowered, due to the side effects associated with PegIFN-alpha-2a is high. We look forward to seeing the sustained virological responses, which will inform us whether PegIFN-lambda could be used as a replacement for PegIFN-lambda in the future."

In the ongoing randomized phase-IIB trial, 526 treatment-naïve HCV patients received ribavirin with weekly subcutaneous PegIFN-alpha-2a – a 180µg dose or PegIFN-lambda – either a 120, 180 or 240µg doses.

In HCV genotype 2 and 3 patients, 180µg of PegIFN-lambda led to 75.9% RVR and 96.6% cEVR, compared to 31% RVR and 86.2% cEVR for the same dose of PegIFNα-2a. PegIFN-lambda exerts its antiviral effects through a different receptor to PegIFN-alpha-2a.1

More information: References

1. Zeuzem S et al. Pegylated Interferon-lambda (PegIFN-λ) shows superior viral response with improved safety and tolerability versus PegIFNα-2a in HCV patients (G1/2/3/4): Emerge Phase IIB through week 12. Abstract presented at The International Liver CongressTM 2011. http://www1.easl.e … rals/422.htm

2. http://www.thebody … art1705.html . Accessed 11.03.2011

Provided by European Association for the Study of the Liver

Early work indicates drug used to treat alcoholism may help those with Fragile X and autism


In small, early clinical trials, adults and children with autism and Fragile X syndrome have shown improved communication and social behavior when treated with acamprosate, according to Craig Erickson, M.D., assistant professor of psychiatry at the Indiana University School of Medicine and chief of the Riley Hospital for Children Christian Sarkine Autism Treatment Center at Indiana University Health.

Acamprosate, which affects chemicals in the brain by blocking certain receptors associated with mental health, has approval from the Food and Drug Administration for the treatment of alcoholism in adults.

Dr. Erickson is the inventor on a pending utility patent for the use of acamprosate as a therapeutic agent for Fragile X syndrome, the most common inherited form of intellectual disability and the most frequent single gene cause of autism.

"We have been treating small numbers of both adults and children," said Erickson. "We have observed improvements in eye contact, social interaction and speech. This is very early work, but it appears promising.

"We have a lot to do. We need to determine appropriate doses and forms for the best drug delivery. Larger studies will be needed to determine effectiveness and tolerability. And we expect to find many interesting things along the road, for example whether this drug could work better in those with Fragile X who have autism than in those whose autism is from an unknown cause."

In November 2010 Dr. Erickson and colleagues reported in the Journal of Autism and Developmental Disorders on the first trial of acamprosate in adults with Fragile X syndrome and autism. In the three patients studied, acamprosate was associated with improved linguistic abilities. During five months of treatment all three showed unexpected marked communication improvement.

In a study supported by the Indiana University Clinical and Translational Sciences Institute, Dr. Erickson is currently recruiting five-to-17-year-old children with Fragile X syndrome to a clinical trial designed to learn if acamprosate reduces various symptoms including inattention, hyperactivity, language impairment, irritability, and social deficits. In addition to investigating the effectiveness and tolerability of acamprosate in youth with Fragile X syndrome, IU School of Medicine researchers are assessing neurobiological differences between Fragile X syndrome and autism spectrum disorders of unknown cause.

Fragile X syndrome is the most common inherited form of developmental disability. Fragile X syndrome is inherited from a carrier parent, most frequently the mother. Up to two thirds of individuals with Fragile X syndrome display evidence of autism spectrum disorders.

"Dr. Erickson's research and work in this area is unique. The Indiana University Research and Technology Corporation has applied for a use patent because, while we are far from definitive knowledge and treatment, as early data is acquired, we believe this drug has real potential as a therapy for both children and adults with autism," said Bradley Fravel, Ph.D., MBA, an IURTC senior technology manager. IURTC works to enhance the research and development capability of Indiana University, creating new Indiana-based companies, and provides support for entrepreneurial development.

Dr. Erickson strongly cautions that while preliminary data on acamprosate in individuals with Fragile X syndrome appears promising, large scale multi-center clinical trials of acamprosate are needed to determine whether it can help those with Fragile X and autism.

Provided by Indiana University School of Medicine

Blood biomarker associated with prevalence, severity of Alzheimer's, but not risk of development


Higher levels in blood of the protein clusterin, also known as apolipoprotein J, are significantly associated with the prevalence and severity of Alzheimer's disease, but not with the risk of onset of new disease, according to a study in the April 6 issue of JAMA.

Clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with Alzheimer disease (AD), and have been suggested to be involved in the pathogenesis of AD. "Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in AD, suggesting its possible use as a biomarker of AD," according to background information in the article.

Elisabeth M. C. Schrijvers, M.D., of Erasmus MC University Medical Center, Rotterdam, the Netherlands, and colleagues examined the associations between plasma levels of clusterin and the prevalence, severity, and risk of AD. The study included analysis of data on plasma levels of clusterin measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random sub-group of 926 participants, and an additional 156 participants diagnosed with AD during follow-up (average, 7.2 years) until January 2007.

The researchers found that the likelihood of prevalent AD increased with increasing plasma levels of clusterin, with the odds increased by 63 percent for every standard deviation increase in clusterin levels, after adjusting for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension. Among patients with AD, higher clusterin levels were associated with more severe disease.

There was no statistically significant association of plasma clusterin levels with new AD during total follow-up or with new AD within or after 3 years of baseline. Results for all-cause dementia and vascular dementia were similar.

"In conclusion, our data from the general population show that increased plasma clusterin levels are associated with prevalent AD and are higher in more severe cases of AD. However, increased levels of clusterin do not precede development of AD and therefore are not a potential early marker of subclinical disease," the authors write.

More information: JAMA. 2011;305[13]1322-1326.

Provided by JAMA and Archives Journals (news : web)