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In The Spotlight-HCV Advocate and Ms. Lucinda K. Porter, RN.

In The News

Novel Hep C Treatment Excludes Peginterferon Alfa
By: DENISE NAPOLI, Internal Medicine News Digital Network
Therapy with a novel nonnucleoside polymerase inhibitor, in combination with a protease inhibitor and ribavirin, achieved a 100% virologic response rate at 29 days among patients with hepatitis C genotype 1, Dr. Stefan Zeuzem and colleagues reported in the December issue of Gastroenterology.

Moreover, this novel alternative to the standard peginterferon alfa regimen was safe, with no serious adverse events, and was highly tolerable, the investigators said.
"This indicates that HCV [hepatitis C virus] can be eradicated in chronically infected patients with a PegIFN-free DAA [direct-acting antiviral agent] combination regimen," the authors wrote.

Dr. Zeuzem, of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues studied 34 adult patients (mean age 51 years) who were naive to interferon, PegIFN, ribavirin, or any DAA for acute or chronic hepatitis C infection.
All patients had plasma HCV RNA levels of at least 100,000 IU/mL at screening and did not have cirrhosis.

Patients with hepatitis B virus, human immunodeficiency virus, previous or ongoing rash or photosensitivity, decompensated liver disease, or hyperbilirubinemia greater than 1.5 times the upper limit of normal were excluded.

Participants were randomized in a 1:1 fashion to receive a thrice-daily 400-mg or 600-mg dose of BI 207127, "an orally bioavailable, reversible, thumb pocket 1 nonnucleoside inhibitor (NNI) of the HCV NS5B polymerase with potent and specific antiviral activity in vitro," according to the authors (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.08.051]).

"This indicates that HCV can be eradicated in chronically infected patients with a PegIFN-free DAA combination regimen."

All participants also received BI 201335, "a second-generation HCV NS3/4A protease inhibitor with highly potent in vitro activity against GT-1a/1b subtypes," wrote the authors, at a dose of 120 mg per day, as well as daily weight-dosed ribavirin, all taken with food, for 4 weeks.
"Drug-resistance studies in cell culture demonstrate that BI 201335 and BI 207127 have different resistance profiles, and previous observations using NS3/4A protease inhibitors and NS5B thumb pocket 1 NNI compounds demonstrate that 2-drug combinations profoundly reduce the selection of drug-resistant variants," explained Dr. Zeuzem.

The researchers found that in the cohort taking the larger, 600-mg doses of the polymerase inhibitor BI 207127, virologic response rates (defined as plasma HCV RNA levels of less than 25 IU/mL) were 18%, 82%, 100%, and 100% at days 8, 15, 22, and 29, respectively.
Slightly less impressive results were seen in the 400-mg group, with rates of 27%, 47%, 67%, and 73% at days 8, 15, 22, and 29 respectively.

Also in the 400-mg cohort, "higher response rates were observed in genotype 1b infected patients, compared with genotype 1a infected patients," wrote the authors, whereas results in the 600 mg group were not contingent on sub-genotypes.

"Most patients in the 600 mg TID [three times a day] dose group even had undetectable HCV RNA at days 22 and 29 (53% and 71%, respectively), while these rates did not exceed 20% in the 400 mg TID dose group," added the investigators.

Looking at safety and tolerability, Dr. Zeuzem and colleagues noted that most patients in both dosing cohorts complained of mild diarrhea, nausea, and vomiting.
Additionally, at the 600-mg dose, 42% developed mild rashes or photosensitivities, they said, and four patients developed "transient and very mild paresthesias of very different localizations."

"However, there were no severe AEs [adverse events], serious AEs or AE-related premature treatment discontinuations within the 4-week study period."
The "crucial next step," according to the investigators, will be achievement of longer-term SVR on the novel peginterferon-free regimen.

"Moreover, eliminating not only PegIFN but also RBV [ribavirin] from future HCV treatment would undoubtedly improve tolerability and would potentially allow for the treatment of patients with RBV contraindications," they added.

Indeed, at the time of this study’s publication, a phase 2b study was ongoing.
Dr. Zeuzem, along with several of his coinvestigators, disclosed financial and consulting relationships with multiple pharmaceutical companies, including the makers of the novel drugs used in this study, Boehringer Ingelheim. Boehringer Ingelheim also funded editorial assistance provided for this article.

Inhibitex Reports Recent Clinical and Corporate Developments
Released: 11/29/11 07:00 AM EST

Inhibitex, Inc. (NASDAQ:INHX) (the “Company”) today announced several recent clinical and corporate developments, including top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin (RBV) for seven days.
“We believe the significant increase in antiviral activity demonstrated with 100 mg INX-189 in combination with RBV, as compared to 100 mg INX-189 dosed as monotherapy, further confirms the antiviral synergy between INX-189 and RBV that we have consistently observed in preclinical and clinical results to-date,” stated Dr. Joseph Patti, Senior Vice President and CSO of Inhibitex, Inc. “We look forward to further exploring this antiviral synergy with 200 mg of INX-189 and expanding the scope of our ongoing and planned Phase 2 clinical trials to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012.”

Recent Corporate Developments
INX-189 for Chronic Hepatitis C – The Company today reported top-line safety and antiviral data from an ongoing Phase 1b extension trial of INX-189, which is designed to further evaluate the safety, tolerability, pharmacokinetics and antiviral activity of various doses of INX-189, administered as monotherapy or in combination with RBV, for seven days in treatment-naïve patients infected with chronic HCV genotype 1. In the ongoing trial, 100 mg INX-189, dosed once-daily for seven days in combination with RBV, continued to demonstrate potent and dose-dependent synergistic antiviral activity with a median HCV RNA reduction from baseline of -3.79 log10 IU/mL. Further, 100 mg INX-189 in combination with RBV was well tolerated and there were no serious adverse events. For comparison purposes, in a clinical trial completed earlier this year, 100 mg INX-189 dosed as monotherapy once-daily for seven days resulted in a median -2.53 log10 IU/mL reduction in HCV RNA levels. In this same clinical trial, the Company also reported antiviral data indicating that INX-189, when dosed once-daily at 9 and 25 mg in combination with RBV for seven days, demonstrated dose-dependent, synergistic antiviral activity.

The Company also reported today that, subject to regulatory review, it plans to further expand its ongoing Phase 1b extension trial to evaluate once-daily doses of 200 mg INX-189 in combination with RBV; 300 mg INX-189 as monotherapy; and 200 mg INX-005 (a single isomer of INX-189) as monotherapy, respectively, for seven days. The Company anticipates that the Phase 1b extension trial will be completed in the first quarter of 2012.

Additionally, the Company reported that it plans to submit a protocol amendment this quarter to its ongoing Phase 2 study in genotype 2 and 3 HCV-infected patients to include the evaluation of 100 mg and 200 mg of INX-189 dosed once-daily in combination with RBV for 12 weeks.
Financing Activity – The Company reported today that it had recently sold a total of 1,949,015 shares of common stock at an average price per share of $10.25 for total gross proceeds of $19,983,396 through its at-the-market (ATM) financing vehicle. The Company entered into a $20 million ATM financing arrangement with McNicoll, Lewis & Vlak LLC (MLV) in November 2010, which provides it the opportunity to sell registered shares into the open market through MLV from time-to-time under its effective shelf registration. After commissions, the Company received $19,383,274 in net proceeds. The intended use of the net proceeds is to support the expansion of the Company’s planned Phase 2 program for INX-189 in 2012 and for general corporate purposes.

About Inhibitex
Inhibitex, Inc. is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company’s clinical-stage pipeline includes two Phase 2 development programs for which it has retained all future rights: INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic HCV infections, and FV-100, a nucleoside analogue in development for the treatment of shingles-associated pain. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM® protein platform to Pfizer for the development of a staphylococcal vaccine, which is currently being evaluated in a Phase 1/2 clinical trial. For additional information about the Company, please visit www.inhibitex.com.

Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding: the Company’s plan to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of additional doses of INX-189 and INX-005, administered as monotherapy or in combination with ribavirin for seven days in its ongoing Phase 1b extension trial; the Company’s plan to submit a protocol amendment to expand the scope of its ongoing and planned Phase 2 development program of INX-189 to include interferon-free combinations in HCV genotype 1, 2, and 3 patients in 2012; the time in which the Company anticipates completing enrollment in its ongoing Phase 1b extension trial; and the intended use of net proceeds from the Company’s recent financing activities, are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk of: the Company, the FDA, a data safety monitoring board, or an institutional review board delaying, limiting, suspending or terminating the clinical development of INX-189 at any time for a lack of safety, tolerability, biologic activity or efficacy, commercial viability, regulatory issues, or any other reason; the safety, tolerability and antiviral results achieved in small numbers of patients to-date not being repeatable in larger scale clinical trials; the Company’s ability to secure and use qualified third-party clinical and preclinical research and data management organizations to assist it in initiating and conducting planned clinical trials; third-party contract manufacturers not fulfilling their contractual obligations or otherwise performing satisfactorily in the future; the Company’s ability to manufacture and maintain sufficient quantities of preclinical and clinical trial material on-hand to complete planned preclinical studies and clinical trials on a timely basis; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2010 and its Quarterly Report on Form 10-Q for the period ended March 31, 2011, June 30, 2011 and September 30, 2011 as filed with the Securities and Exchange Commission, or SEC, on March 16, 2011, May 6, 2011, August 9, 2011 and November 8, 2011, respectively. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.
There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.
Inhibitex® and MSCRAMM® are registered trademarks of Inhibitex, Inc.

Contacts:Inhibitex, Inc.Russell H. Plumb, 678-746-1136Chief Executive Officerrplumb@inhibitex.com


The American Association for the Study of Liver Diseases
San Francisco 2011 Nov 6-9AASLD
From NATAP

AASLD: Preclinical Characterization of a Series of Highly Potent Achiral Phosphorodiamidate Nucleotide Analogue Inhibitors of Hepatitis C Polymerase
- (11/30/11)
AASLD: Cost-Effectiveness of Boceprevir Use in Patients with Chronic Hepatitis C Genotype-1 Who Failed Prior Treatment with Peginterferon/Ribavirin
- (11/28/11)


From GastroHep

Prescriptions for chronic abdominal pain
study in this month's issue of the Clinical Gastroenterology & Hepatology investigates the frequency of opioid prescriptions for abdominal pain in outpatient clinics in the USA.Opioids are sometimes used to treat chronic abdominal pain. However, opioid analgesics have not been proven to be an effective treatment for chronic abdominal pain and have been associated with drug misuse, constipation, and worsening abdominal pain.

Dr Spencer Dorn and colleagues estimated the national prescribing trends and factors associated with opioid prescribing for chronic abdominal pain.Chronic abdominal pain-related visits by adults to US outpatient clinics were identified using reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey.

Data were weighted to produce national estimates of opioid prescriptions over time.Logistic regression analyses, adjusted for complex survey design, were performed to identify factors associated with opioid use.The prevalence of visits for which an opioid was prescribed increased to 12% in 2008Clinical Gastroenterology & Hepatology

The research team found that the number of outpatient visits for chronic abdominal pain consistently decreased over time from 14.8 million visits in 1997 through 1999 to 12.2 million visits or 1863 visits per 100,000 population in 2006 through 2008.Conversely, the adjusted prevalence of visits for which an opioid was prescribed increased from 6% in 1997 through 1999 to 12% in 2006 through 2008.The team found that opioid prescriptions were most common among patients aged 25 to 40 years old.The researchers observed that opioid prescriptions were less common among uninsured, and African American patients.

Dr Dorn's team commented, "From 1997 to 2008 opioid prescriptions for chronic abdominal pain more than doubled.""Further studies are needed to better understand the reasons for and consequences of this trend."Clin Gastroenterol Hepatol 2011: 9(12): 1078-108501 December 2011

Clinical prediction rule and platelet count predict esophageal varices in children
This month's issue of Gastroenterology identifies predictors of esophageal varices in children.

The validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive.

Dr Juan Cristóbal Gana and colleagues from Chile measured the ability of a previously developed noninvasive clinical prediction rule to predict the presence of esophageal varices in children.

The researchers analyzed data from 108 children, younger than age 18, who received endoscopies at 8 centers, to assess portal hypertension from chronic liver disease or portal vein obstruction.

Blood test and abdominal ultrasound scan results were obtained within 4 months of endoscopy.69% had esophageal varices

Gastroenterology
Grading of varices identified by endoscopy was confirmed by independent blinded review.Spleen size, based on data from the ultrasound scan, was expressed as a standard deviation score relative to normal values for age.

Of the children studied, 69% had esophageal varices, including 32% with large varices.The researchers observed that the best noninvasive predictors of esophageal varices of any size included platelet-to-spleen size z-score ratio, clinical prediction rule, and platelet count.

The research team found that positive predictive values for the clinical prediction rule, and platelet counts were 0.87 and 0.86, respectively.

The negative predictive values for clinical prediction rule and platelet counts were 0.64 and 0.63, the positive likelihood ratios were 3.06 and 2.76, and the negative likelihood ratios were 0.64 and 0.63, respectively.

The team observed that based on positive and negative predictive values, the most accurate noninvasive tests were the clinical prediction rule and platelet counts.

Dr Gana's team comments, "Noninvasive tests such as clinical prediction rule and platelet count can assist in triaging children for endoscopy to identify esophageal varices."Gastroenterol 2011: 141(6): 2009-201601 December 2011

Platelet count predicts fibrosis in NAFLD
A study in the most recent issue of the Journal of Gastroenterology examines the use of platelet counts in predicting fibrosis in NAFLD.

The severity of liver fibrosis is known to be a good indicator for surveillance, and for determining the prognosis and optimal treatment of nonalcoholic fatty liver disease (NAFLD).

However, it is virtually impossible to carry out liver biopsies in all NAFLD patients.Dr Masato Yoneda and colleagues investigated the clinical usefulness of measuring the platelet count for predicting the severity of liver fibrosis in a large retrospective cohort of Japanese patients with NAFLD.

A total of 1048 patients with liver-biopsy-confirmed NAFLD seen between 2002 and 2008 were enrolled from 9 hepatology centers in Japan. The area under the curve for diagnostic performance for Stage 4 was 0.92Journal of GastroenterologyLaboratory evaluations were performed for all patients.A linear decrease of the platelet count with increasing histological severity of hepatic fibrosis was revealed.

The area under the receiver operating characteristic curve estimating the diagnostic performance of the platelet count for hepatic fibrosis Stage 3 was 0.77, and that for Stage 4 was 0.92.Dr Yoneda's team concluded, "The platelet count may be an ideal biomarker of the severity of fibrosis in NAFLD patients, because it is simple, easy to measure and handle, cost-effective, and accurate for predicting the severity of fibrosis.""Furthermore, by using the platelet count cutoff value validated in our multiple large trials, efficient recruitment of NAFLD patients may be facilitated."J Gastroenterol 2011: 46(11): 1300-130630 November 2011


Studies of patients with cirrhosis uncover limitations in liver cancer screening
Two studies available in the December issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, have uncovered limitations in screening for primary liver cancer, also known as hepatocellular carcinoma (HCC). The first study found that, if given the choice during a clinical trial, most patients with cirrhosis prefer surveillance over the possibility of non-screening, therefore making a randomized study of HCC screening not feasible. A second study determined that ultrasonographic screening at three monthly versus six monthly intervals did not improve the detection of small liver cancers.


Green tea flavonoid may prevent reinfection with hepatitis C virus following liver transplantation
German researchers have determined that epigallocatechin-3-gallate (EGCG)—a flavonoid found in green tea—inhibits the hepatitis C virus (HCV) from entering liver cells. Study findings available in the December issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, suggest that EGCG may offer an antiviral strategy to prevent HCV reinfection following liver transplantation.

Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis
The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.)



Newsletter
The HCV Advocate Newsletter, December 2011

In This Issue:
HCV Snapshots: A Summary of AASLD 2011

Alan Franciscus, Editor-in-Chief
HealthWise: Free from Hepatitis C

Lucinda K. Porter, RN
Book Review: Free from Hepatitis C

Rose Christensen

Hep C deaths outpace HIV; new drugs, services for coinfected
Deaths related to hepatitis C have outpaced those due to HIV/AIDS since 2007, researchers reported at the American Association for the Study of Liver Diseases meeting earlier this month in San Francisco.

Czech researcher on trail of liver cirrhosis treatment

Young Czech researcher’s work could lead to drug to help prevent often fatal liver failure, but it’s no green light for heavy drinkers

A young Czech medical researcher is investigating a promising treatment for those suffering from liver cirrhosis, probably after years after years of above average alcohol consumption, and who are risking their lives from complete liver failure as a result.
Jan Petrášek, who is based at Prague’s prestigious Institute for Clinical and Experimental Medicine (IKEM) but currently carrying out research at the University of Massachusetts in the U.S, has made the discovery that a drug commonly used for the treatment of rheumatoid arthritis also seems to help those suffering from cirrhosis by helping the liver to function properly.

Lab tests carried out on animals have given promising results and research has now switched to whether the promising treatment can be used on humans, according to a report in Wednesday’s edition of the paper Lidové noviny.......