HCV Advocate EASL 2008 Coverage

 

 

 

Liver Diseases: A Huge European Health Burden, But Some Trends Are Positive

http://www.prnewswire.co.uk

 

  • 29 Million EU Citizens (6%) Have Liver Diseases, 5th Most Common Cause of Death
  • Yearly, Liver Cancer Alone Takes 40,000 Lives; Alcohol Abuse Takes 13,000
  • Number With Fatty Liver Disease Stable or Growing; Viral Hepatitis Declines

 

More than 6,000 physicians and scientists from around the world gathered today in this historic Italian city to attend the opening sessions of the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), which runs until April 27th. Not surprisingly, several of the first presentations focused on trends in the prevalence of each of the major liver diseases, including continuing declines in new cases of hepatitis B and C, but stability or increases in fatty liver disease due either to excessive consumption of alcohol or non-alcoholic causes (NAFLD - non-alcoholic fatty liver disease).

 

Hepatologists (liver disease specialists) study and treat a variety of acute and chronic conditions affecting this largest internal organ of the body. The acute category includes diseases that typically result from inflammation or infection due to injurious agents such as viruses, alcohol, and drugs. The most prominent conditions - each of which may arise in an acute form but then progress to a chronic state -- are alcoholic liver disease; hepatitis B, C, and D; non-alcoholic fatty liver disease (NAFLD); and NASH (non-alcoholic steatohepatitis, the most severe subset of NAFLD).

 

The transition from an acute to a chronic state occurs when the patient fails to recover and the acute infection or disease produces ongoing damage to the liver. Cirrhosis - which refers to the death of liver cells, altered cell regeneration, deposition of fibrous scar tissue, and ultimately the impairment of liver function - represents the final stage of many chronic liver diseases. Cirrhosis can only partially be reversed, but treatments can stop or slow its progression. When uncontrollable complications of cirrhosis occur, or when damage precludes sufficient liver function, a liver transplant becomes necessary. Cirrhosis is the major risk factor for the development of hepatocellular carcinoma (HCC), a primary cancer of liver cells, which may also require transplantation.

 

Estimates suggest 10 million carriers of viral hepatitis in Europe, of which over 8 million are infected with HCV. Although statistics vary widely by country, HCV accounts for a large (or in some countries, majority) proportion of all cases of cirrhosis and HCC. Although precise figures are not available, alcoholic liver disease is a growing problem in both Western and Eastern Europe, in part because of changing lifestyles and the increasing numbers of women and adolescents who drink to excess (a problem that in the past was largely a phenomenon of adult males). The Dionysos study, conducted in Northern Italy, reported that 4% of the population had alcoholic liver disease of varying severity. Alcoholic liver disease is the second most common indication for liver transplantation, after HCV. NAFLD and NASH denote fatty infiltration of the liver that are not due to excessive alcohol, and are related instead to insulin resistance, type 2 diabetes, obesity, and the metabolic syndrome. These abnormalities are now receiving considerable attention not only because they may progress to liver cirrhosis, but also as additional risk factors for cardiovascular disease. The best current estimates suggest that in the general population NAFLD can be found in 3% to 24% of adults.

 

Despite improved prevention, diagnosis, and treatment, the overall costs of liver disease remain very high because of an increase prevalence of selected conditions, and the common progression to a chronic state possibly leading to life-threatening complications.

 

About EASL

The European Association for the Study of the Liver (EASL) aims to promote investigation into liver disease and improve the treatments that currently exist for these conditions. The association, through its annual meetings, seeks to inform and educate both the scientific community as well as society in general about the increasing occurrence of liver diseases along with the importance of understanding these conditions in order to treat and prevent them. Since its creation in 1966, the EASL congress has been hosted in 20 different European countries. Currently the association has over 1400 members and the annual congress attracts over 6000 delegates from over 65 countries each year.

 

Study shows positive findings in treating patients with advanced hepatitis C

http://www.eurekalert.org

 

MILAN, ITALY, April 24, 2008 – The hepatitis C therapy peginterferon alfa-2b, when given as low-dose maintenance therapy, can prevent disease progression in certain patients who failed previous interferon-based hepatitis C therapies and have advanced liver disease, according to findings from a large, four-year study presented today at the 43rd annual meeting of the European Association for the Study of the Liver (EASL).

 

The study, called COPILOT (COlchicine versus Peg-Intron LOng-Term), showed that low-dose peginterferon alfa-2b was superior to colchicine in improving the disease-free survival of patients with cirrhosis and portal hypertension, especially in patients who stayed on treatment. In the study, more than 40 percent of patients had portal hypertension, a condition of high blood pressure in the major vessel going to the liver from the gastrointestinal tract and which often accompanies liver cirrhosis. However, peginterferon alfa-2b maintenance therapy was not superior to colchicine in patients overall.

 

“These findings make a strong case for considering low-dose peginterferon alfa-2b as a maintenance therapy in patients with cirrhosis and portal hypertension who have failed hepatitis C eradication therapy,” said principal investigator Nezam Afdhal, M.D., Chief of Hepatology at Beth Israel Deaconess Medical Center (BIDMC) and Associate Professor of Medicine at Harvard Medical School. “While other interferon maintenance therapies have been studied in the past few years in previous interferon nonresponders, these findings show, for the first time, a clinical benefit in a specific population with advanced disease,” he said.

 

Hepatitis C virus (HCV) infection is transmitted through exposure to infected blood and affects an estimated 4 million individuals in the United States. The current standard treatment, combination therapy with pegylated interferon plus ribavirin for 24 to 48 weeks, can eradicate the virus in about 50 percent of patients. Those who do not respond and have cirrhosis are at far greater risk for developing liver cancer or liver failure, so the development of treatment strategies for these nonresponders is a priority.

 

Conducted at approximately 40 sites in the United States, the COPILOT study compared weight-based low-dose peginterferon alfa-2b (subcutaneous injection of 0.5 mcg/kg/wk, one-third the dose used in standard HCV combination therapy) versus colchicine (0.6 mg orally, twice daily), an anti-inflammatory and antifibrotic medication, in 555 chronic hepatitis C patients with advanced liver fibrosis who previously failed interferon-based therapies. Patient baseline characteristics were well balanced between the two study arms. Over the four years of the randomized study, investigators monitored the patients to determine how many reached a primary endpoint, defined as death, liver transplant, hepatocellular carcinoma (liver cancer), variceal bleeding, or liver failure (increase in Child-Pugh-Turcotte [CPT] by 2 points with ascites, jaundice or encephalopathy). They analyzed their findings for all 555 patients, who received at least one dose of their assigned drug, in two ways: based on all events that occurred during the entire four years of the study, regardless of whether a patient was still taking their assigned drug or not (the “intent-to-treat” or ITT analysis), and based on only the events that occurred while patients were taking their assigned drug (the “on drug” analysis).

 

The investigators found a primary endpoint was reached by 17.8% (51/286) of patients in the peginterferon alfa-2b group versus 20.4% (55/269) in the colchicine group in the ITT analysis, and by 12.2% (35/286) and 16.0% (43/269) patients, respectively, in the on-drug analysis (treatment differences were not statistically significant). Among patients who had portal hypertension (42.3% and 48.0% of patients in the peginterferon alfa-2b and colchicine groups, respectively), peginterferon alfa-2b therapy resulted in significantly improved event-free survival in both the ITT and on-drug analyses (Wilcoxon p = 0.041 and 0.028, respectively). Further, variceal bleeding, a specific complication of portal hypertension, was almost abolished with peginterferon alfa-2b in both the ITT (10 vs. 1 patients) and the on-drug (10 vs. 0 patients) analyses. In the ITT analysis, hepatocellular carcinoma occurred in 7.7% and 5.9% of patients in the peginterferon alfa-2b and colchicine groups, respectively, a non-significant difference.

 

Overall, 49% of patients discontinued their medication before the end of the four-year study, with 36% due to failure to comply and 13% due to side effects. Peginterferon alfa-2b was generally well tolerated. Among patients who discontinued due to interferon side effects (17.1%, 49/286), the most common reason (45%, 22/49 patients) was general intolerance to interferon (e.g., due to flu-like symptoms, malaise, and other common interferon side effects).

 

###

The COPILOT study was supported by Schering-Plough Corporation, manufacturer of peginterferon alfa-2b.

 

Biolex Therapeutics Researchers Present Locteron(R) Phase 2a Hepatitis C Trial Results at EASL Conference 

http://www.earthtimes.org

 

PITTSBORO, NC -- 04/24/08 -- Biolex Therapeutics, Inc. announced that the results from its SELECT-1 Phase 2a clinical trial of Locteron® will be presented today at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL). As a controlled-release interferon alfa, Locteron is designed to improve patient care through a more favorable side-effect profile compared to existing pegylated interferon products and Albuferon®, each of which lacks a controlled-release mechanism.

 

SELECT-1 was a twelve-week trial in 32 treatment-naive patients chronically infected with the genotype-1 variant of the hepatitis C virus. The Phase 2a trial was designed to evaluate four doses of Locteron administered once every two weeks in combination with the antiviral drug ribavirin. In the SELECT-1 trial, Locteron demonstrated a strong anti-viral response with 100% of the patients in the two highest dose groups achieving early virologic response. Viral kinetic modeling of the SELECT-1 results by Eva Herrmann, Ph.D. of Saarland University, Homburg/Saar, Germany and Stefan Zeuzem, M.D. of JW Goethe-University Hospital, Frankfurt/Main, Germany, demonstrated a statistically significant dose response. Updated results presented at the EASL meeting also included the effect of Locteron on biomarkers and alanine aminotransferase (ALT), each of which showed a dose-dependent response to Locteron.

 

SELECT-1 Results Presented Today at EASL Conference

The SELECT-1 results will be presented today at the EASL conference in a poster titled "Viral Kinetics during Treatment with a Controlled-Release Recombinant Interferon Alfa-2b in Genotype 1 Chronic Hepatitis C Patients." Anti-viral results for the SELECT-1 trial were as follows:

 

·        The percentage of patients who achieved early virologic response (EVR), defined as at least a two-log reduction in hepatitis C virus, was 100% in the 640 and 480 µg dose cohorts and 88% in the 320 µg dose cohort, compared to 37.5% in the 160 µg dose cohort.

·        A clear dose response was observed in the study, and viral kinetic modeling by Drs. Herrmann and Zeuzem demonstrated statistically significant HCV RNA reduction during the entire 12-week treatment period.

·        Average viral reduction after 12 weeks of treatment ranged from 4.7 to 4.2 logs for the 640, 480 and 320 µg doses, compared to 1.8 logs for the lowest dose of 160 µg.

·        Locteron was generally well tolerated at all doses. There were no serious adverse events in the 160 µg, 320 µg, and 480 µg cohorts.  There was one serious adverse event in the 640 µg cohort, a case of otitis, or inflammation of the ear, which resolved.

·        Over 90% of the adverse events that were experienced were rated as mild.

 

The SELECT-1 trial also measured certain biomarkers, the results of which were as follows:

 

·        Locteron resulted in a dose-dependent reduction in alanine aminotransferase (ALT), an enzyme released by the liver into the blood when the liver is damaged.

·        Locteron resulted in a dose-dependent increase in oligoadenylate synthetase (OAS) and neopterin, markers commonly associated with the biological effects of interferon alfa.

 

Locteron Overview

As a controlled-release interferon alfa, Locteron is designed to improve patient care through a more favorable side-effect profile compared to existing pegylated interferon products and Albuferon (albumin-fused interferon), each of which lack a controlled-release mechanism. Locteron combines BLX-883, a recombinant interferon alfa produced by Biolex in its patented LEX System(SM), with PolyActive(TM), an advanced controlled-release drug delivery technology developed by OctoPlus. Locteron is configured to allow dosing once every two weeks, an improvement in patient convenience compared to currently marketed pegylated interferon alfa products that require dosing every week. More importantly, Locteron's controlled-release mechanism results in the gradual release of interferon alfa to patients over the duration of two weeks. This controlled-release mechanism is designed to cover inter-dose troughs which may contribute to the frequency, duration and severity of side effects, including flu-like symptoms, commonly experienced by patients treated with currently marketed pegylated interferons and with Albuferon. Biolex is co-developing Locteron with its partner OctoPlus N.V.

 

In February 2008, Biolex announced the commencement of patient dosing in a U.S. Phase 2a clinical trial of Locteron in hepatitis C. The U.S. "PLUS" Phase 2a trial is designed to expand upon the favorable results from the SELECT-1 trial reported above and to provide U.S. investigators first-hand experience with Locteron.

 

Locteron is an investigational therapeutic candidate and has not been approved for sale by the United States Food and Drug Administration or by any international regulatory agency.

 

Pharmasset Adds Two Cohorts to R7128 Hepatitis C Study

http://www.earthtimes.org   

 

-- Two 4-week cohorts will be enrolled to evaluate R7128 1500mg BID in HCV genotypes 2 and 3 prior non-responders and R7128 1000mg BID in HCV genotype 1 treatment-naive patients --

 

PRINCETON, N.J. and MILAN, Italy, April 24  /PRNewswire-FirstCall/ -- Pharmasset, Inc.  will enroll two additional cohorts in the on- going Phase 1 study protocol to evaluate 4 weeks of combination therapy with R7128.  R7128, a prodrug of PSI-6130, is a nucleoside analogue polymerase inhibitor of hepatitis c virus (HCV) that is being developed through Pharmasset's collaboration with Roche.

 

Cohort 3 will study R7128 1000mg BID in treatment-naive patients with HCV genotype 1.  This cohort is intended to provide clinical antiviral activity data in support of pharmacokinetic models from earlier studies.  Cohort 4 will study R7128 1500mg BID in patients with HCV genotypes 2 and 3 who did not achieve a sustained virologic response (SVR) with previous interferon-based therapy.  Cohorts 3 and 4 will both be dosed in combination with Pegasys (peginterferon alfa-2a) plus Copegus (ribavirin).

 

Patients in Cohorts 3 and 4 are scheduled to begin dosing by the end of May 2008.  Preliminary safety and antiviral activity data from the 4-week combination studies are anticipated during the 3rd quarter of 2008.  Cohorts 3 and 4 will be conducted in parallel with the global Phase 2b study preparation activities for R7128.  The timing of the Phase 2b study is not dependent upon data from Cohorts 3 and 4.

 

"Our pharmacokinetic modeling of the 500mg and 1500mg cohorts of R7128 in combination with Pegasys plus Copegus suggests that the 1000mg dose could deliver a rapid virologic response (RVR) rate similar to the 1500mg dose," stated Dr. Michelle Berrey, Pharmasset's Chief Medical Officer.  "The confirmatory results from this additional cohort will aid us in selecting the appropriate doses to evaluate in the global Phase 2b study that is being planned to evaluate R7128 in triple combination for up to 12 weeks."

 

"R7128 is equally potent in vitro against HCV genotypes 1, 2, 3 and 4, and we believe it is clinically and commercially important to test R7128 in patients with these HCV genotypes," stated Schaefer Price, Pharmasset's Chief Executive Officer.  "Twenty percent of U.S. HCV-infected patients and approximately 30% of European and Latin American HCV-infected patients have genotypes 2 and 3.  These patients are currently treated with 24 weeks of pegylated-interferon plus ribavirin, but 20% of this population fails to achieve an SVR.  By potentially addressing this unmet medical need in a patient population for whom the standard of care is only 24 weeks, we could possibly design shorter clinical trials that may provide a quicker path to the market for R7128."

 

Separately, the results of the 4-week Phase 1 clinical trial evaluating two oral dose levels of R7128 (500mg and 1500mg) in combination with Pegasys plus Copegus in 50 treatment-naive patients chronically infected with HCV genotype 1 will be presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) in Milan, Italy on Friday, April 25, 2008 at 11:15 AM ET (US) and 5:15 PM CEST (Milan).  The scientific presentation will be available for download in PDF format immediately following the EASL presentation in the "Events & Presentations" section of the Investor Center on Pharmasset's website at http://investor.pharmasset.com/events.cfm.

 

Please see http://www.clinicaltrials.gov/ or e-mail clinicaltrials@pharmasset.com for more information.

 

Conference Call

Pharmasset will host a conference call at 1:00 PM ET (US) and 7:00 PM CEST (Milan) on Friday, April 25, 2008 to discuss the addition of two R7128 cohorts, as well as the results of the 4-week combination study of R7128 presented at EASL.

 

Dial-in Information:

US/Canada Toll-Free callers: +1 (877) 545-1490

US/Canada Toll or International Toll callers: +1 (719) 325-4884

 

Live audio of the conference call will be simultaneously broadcast over the internet via a webcast.  To access the live webcast, log on to the "Events & Presentations" section of the Investor Center on Pharmasset's corporate website at http://investor.pharmasset.com/events.cfm.

 

Please connect to the company's website at least ten minutes prior to the start of the presentation to ensure adequate time for a reliable connection and any software download that may be necessary to listen to the webcast. The archived replay of the webcast will be available on the Pharmasset website for two weeks following the conference call.

 

About R7128

R7128 is being developed for the treatment of chronic HCV infection. R7128 is a prodrug of PSI-6130, a cytidine nucleoside analog inhibitor of HCV RNA polymerase. A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. Results from an oral single ascending dose study of PSI-6130 in 24 healthy male volunteers showed that PSI-6130 was generally well tolerated with no serious adverse events in doses up to 3000 mg.

 

R7128 demonstrated potent, dose-dependent antiviral activity across four prior treatment-failure patient cohorts (n=40) receiving 750 mg or 1500 mg administered either once-daily or twice-daily for 14 days as monotherapy.  The greatest mean decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg twice-daily, the highest dose of R7128 administered in the study.  These patients demonstrated a mean 2.7 log10 IU/mL (>99%) decrease in HCV RNA.  There was no evidence of the development of viral resistance in any dose cohort after 14 days of dosing.

 

In a 4-week Phase 1 combination study that was conducted in 50 treatment- naive patients chronically infected with HCV genotype 1, R7128 demonstrated potent short-term antiviral activity and was generally safe and well tolerated. Eighty-five percent (85%) of patients receiving R7128 1500mg twice- daily (BID) with Pegasys plus Copegus for 4 weeks achieved undetectable HCV RNA levels with safety and tolerability comparable to placebo with Pegasys plus Copegus.

 

Vertex reports promising hepatitis C drug results

http://www.reuters.com

By Deena Beasley

 

LOS ANGELES, April 23 (Reuters) - Vertex Pharmaceuticals Inc (VRTX.O: Quote, Profile, Research) on Wednesday said early trial results show that its experimental hepatitis C treatment controlled or eradicated the virus in more than 80 percent of patients for whom previous treatment had failed.

 

The ongoing study involves only patients with chronic hepatitis C who were unable to achieve control of the serious liver disease with the standard treatment of pegylated interferon and ribavirin.

 

Vertex said interim results from the open-label trial found that 49 of 60 patients treated with three-times-a-day telaprevir in combination with the other two drugs showed a high rate of viral response after four weeks.

 

"We are shooting for a cure to the disease," said Kurt Graves, chief commercial officer at Vertex.

 

The company said the response appears to have been maintained, with no viral breakthrough, in the 36 patients who have completed 4 weeks of treatment and continued out to 8 weeks and in the 16 patients who have continued to 12 weeks of treatment.

 

"While early, these results are very promising. Patients who have not achieved sustained viral response with prior treatment represent the largest unmet medical need in hepatitis C," Dr. Fred Poordad, chief of hepatology at Cedars-Sinai's liver disease center in Los Angeles, and the study's lead investigator.

 

He said only 10 percent to 15 percent of patients have their virus eradicated when re-treated with current therapies.

 

The trial results were presented in Milan at a meeting of the European Association for the Study of the Liver.

 

Hepatitis C is a blood-borne disease that can cause chronic liver disease, liver cancer and cirrhosis. It affects roughly 170 million people worldwide.

 

Side effects of telaprevir include fatigue, nausea, headache and rash.

 

Vertex said nine patients dropped out of the trial before 12 weeks, including five whose viral loads did not drop far enough and two who experienced viral breakthrough. One patient discontinued treatment due to rash and one discontinued due to inflammation of the chest cavity.

 

Telaprevir is designed to block HCV protease, an enzyme essential for the virus to replicate.

 

Earlier trials in previously-untreated patients found that the drug eradicated the virus in more than 60 percent of patients -- a rate about 20 percent higher than that seen with current therapies.

 

Graves said Vertex is also testing a twice-daily regimen of telaprevir and expects to have interim results in May from a 440-patient trial testing the drug in patients not cured by prior interferon-based therapy.

 

The company also expects to complete late this year enrollment in a pivotal phase 3 trial of telaprevir in treatment-naive patients. (Editing by Carol Bishopric)

 

Pharmasset Presents Results of 4-Week Combination Study of R7128 for the Treatment of Chronic Hepatitis C

http://biz.yahoo.com

 

  • 85% of patients achieve undetectable HCV RNA levels following 4 weeks of treatment with R7128 1500mg BID with Pegasys(R) plus Copegus(R) -
  • Safety and tolerability comparable to placebo administered with Pegasys plus Copegus -
  • EASL presentation available on Pharmasset website -
  • Conference call scheduled for Friday, April 25, 2008 at 1:00 PM ET (US) and 7:00 PM CEST (Milan) -

 

PRINCETON, N.J. and MILAN, Italy, April 25 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS - News) announces the results of a 4-week Phase 1 clinical trial evaluating two oral dose levels of R7128 in combination with Pegasys (pegylated interferon) plus Copegus (ribavirin) in 50 treatment-naive patients chronically infected with hepatitis C virus (HCV) genotype 1. R7128, a prodrug of PSI-6130, is a nucleoside analogue polymerase inhibitor of HCV that is being developed through Pharmasset's collaboration with Roche. The results of this study were presented today at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) being held from April 23-27, 2008 in Milan, Italy.

 

In this study, R7128 demonstrated potent short-term antiviral activity and was generally safe and well tolerated. Eighty-five percent (85%) of patients receiving R7128 1500mg twice-daily (BID) with Pegasys plus Copegus for 4 weeks achieved undetectable HCV RNA levels with safety and tolerability comparable to placebo with Pegasys plus Copegus.

 

Dr. John McHutchison, professor of medicine at Duke University Medical Center and a clinical investigator for this study, stated, "R7128, in combination with Pegasys plus Copegus, has demonstrated Rapid Virologic Response (RVR) percentages in a 4-week study that are similar to HCV protease inhibitors and has an encouraging short-term clinical safety profile. Longer-term studies of R7128 with Pegasys plus Copegus are needed to provide additional information about its potential to improve sustained virologic response (SVR) rates for HCV patients."

 

R7128 4-week Combination Study Overview

The 4-week Phase 1 combination clinical trial was a multiple center, observer-blinded, randomized and placebo-controlled study that was conducted in 50 treatment-naive patients chronically infected with HCV genotype 1. The primary objective was to assess the safety, tolerability and pharmacokinetics of R7128 in combination with Pegasys plus Copegus. The secondary objective was to evaluate the change in HCV RNA after 4 weeks of treatment.

 

The study investigated two oral dose levels of R7128, 500mg and 1500mg, each administered twice-daily (BID) with once-weekly injections of Pegasys plus Copegus BID. Each cohort of 25 patients was comprised of 20 patients receiving R7128 and 5 patients receiving placebo with Pegasys plus Copegus.

 

Antiviral Activity Summary

 

Placebo +

Pegasys plus

Copegus

(n=10)

 

R7128 500mg +

Pegasys plus

Copegus

(n=20)

R7128 1500mg +

Pegasys plus

Copegus

(n=20)

Mean Decrease in HCV RNA (log10 IU/mL)

at 4 Weeks

-2.95

-3.82

-5.12

Percentage of Patients with Undetectable

HCV RNA (<15 IU/mL)

at 4 Weeks (RVR)

10%

30%

85%

 

Potent antiviral activity was demonstrated following 4 weeks of treatment with R7128 1500mg BID with Pegasys plus Copegus. These patients achieved a mean 5.12 log10 IU/mL decrease in HCV RNA and 85% (17 of 20) had undetectable levels of HCV RNA (<15 IU/mL), or RVR. Following 4 weeks of treatment with R7128 500mg BID with Pegasys plus Copegus, patients achieved a mean 3.82 log10 IU/mL decrease in HCV RNA and 30% (6 of 20) had RVR. Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.95 log10 IU/mL decrease in HCV RNA and 10% (1 of 10) had RVR. The baseline HCV RNA levels for all patients in the study were greater than 6.3 log10 IU/mL and were similar across all study groups.

 

Safety Summary

Safety and tolerability for the 4-week treatment period were similar for R7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment period, and most of the adverse events reported were of mild to moderate intensity. The most common adverse events, reported in 15% or greater of patients in any treatment group during the 4-week treatment period, were headache, injection site reaction, myalgia, fatigue, chills, rash, nausea, diarrhea, arthralgia, pyrexia, dizziness, dyspepsia and pruritis. The frequency and severity of these adverse events, as well as any general body system observations, were generally similar to clinical experience with the standard of care for HCV, pegylated interferon plus ribavirin.

 

Grade 3/4 neutropenia was observed in 30% of the placebo patients and in 10% to 15% of the R7128 patients in each active dosing cohort. Grade 3 changes in hemoglobin were observed in 10% of the placebo patients and in 15% of the R7128 patients. There were no clinically significant changes in other hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms.

 

Overall, there was no clinical evidence of any major organ toxicities related to R7128. One patient in the active treatment group discontinued the study during the 4 week treatment period due to lower-gastrointestinal adverse events. At the time of study discontinuation, this patient had undetectable HCV RNA. R7128 was generally safe and well-tolerated when administered for 4 weeks in combination with Pegasus plus Copegus in patients with HCV genotype 1.

 

Please see www.clinicaltrials.gov  or e-mail clinicaltrials@pharmasset.com  for more information.

 

Conference Call

Pharmasset will host a conference call at 1:00 PM ET (US) and 7:00 PM CEST (Milan) on Friday, April 25, 2008 to discuss the R7128 500mg and 1500mg combination study results, as well as the addition of two R7128 cohorts to the on-going Phase 1 protocol.

 

Dial-in Information:

US/Canada Toll-Free callers: +1 (877) 545-1490

US/Canada Toll or International Toll callers: +1 (719) 325-4884

 

Live audio of the conference call will be simultaneously broadcast over the internet via a webcast. To access the live webcast, log on to the "Events & Presentations" section of the Investor Center on Pharmasset's corporate website at http://investor.pharmasset.com/events.cfm .

 

Please connect to the company's website at least ten minutes prior to the start of the presentation to ensure adequate time for a reliable connection and any software download that may be necessary to listen to the webcast. The archived replay of the webcast will be available on the Pharmasset website for two weeks following the conference call.

 

About R7128

 

R7128 is being developed for the treatment of chronic HCV infection. R7128 is a prodrug of PSI-6130, a cytidine nucleoside analog inhibitor of HCV RNA polymerase. A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. Results from an oral single ascending dose study of PSI-6130 in 24 healthy male volunteers showed that PSI-6130 was generally well tolerated with no serious adverse events in doses up to 3000 mg.

 

R7128 demonstrated potent, dose-dependent antiviral activity across four prior treatment-failure patient cohorts (n=40) receiving 750 mg or 1500 mg administered either once-daily or twice-daily for 14 days as monotherapy. The greatest mean decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg twice-daily, the highest dose of R7128 administered in the study. These patients demonstrated a mean 2.7 log10 IU/mL (>99%) decrease in HCV RNA. There was no evidence of the development of viral resistance in any dose cohort after 14 days of dosing.

 

Data On Investigational Compounds Being Co-Developed By Tibotec For The Treatment Of Chronic Hepatitis C Presented At EASL 2008

http://www.medicalnewstoday.com

 

Tibotec BVBA, a global pharmaceutical company dedicated to the discovery and development of innovative drugs that fight infectious diseases, is now building a portfolio of novel antiviral therapies to treat hepatitis C virus (HCV). The investigational protease inhibitors (PI), telaprevir (VX-950) and TMC435350, are being co-developed by Tibotec with Vertex and Medivir, respectively. Data on these compounds will be presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) in Milan, Italy.

 

According to the World Health Organization, an estimated 170 million persons globally are chronically infected with HCV and three to four million persons are newly infected each year.[i] Chronic infection with HCV, a viral infection of the liver, can lead to cirrhosis and liver cancer, and is the most common cause of liver transplant in Europe.[ii],[iii] The current standard of care for HCV patients, treatment with pegylated interferon combined with ribavirin, is effective in thirty to fifty percent of patients with genotype-1 HCV, the most common type globally.[iv] However, treatment with this regimen can cause significant side effects and no effective treatment regimen has been identified for those patients that have failed treatment, sometimes known as non-responders.[v],[vi] The development of new therapies, particularly direct antivirals with different modes of action, will allow HCV patients to undergo a more effective treatment regimen.[vii],[viii]

 

"Our goal is to develop and bring to market new direct antivirals for the treatment of hepatitis C that have significant advantages over the existing standard of care," said Roger Pomerantz, MD, President of Tibotec Research and Development.

 

As a global virology leader committed to patient care, Tibotec uses innovative science and expertise and works with partners to research, develop, manufacture, and market drugs of unmet need. To date, Tibotec has brought to market PREZISTATM (darunavir), an antiretroviral medication for treatment-experienced patients with HIV, and has submitted a marketing application for its second HIV medication, INTELENCETM (etravirine), to the European Agency for the Evaluation of Medicinal Products (EMEA). Its promising pipeline comprises potential treatments for infectious diseases including HIV, tuberculosis, and HCV.

 

Telaprevir: Key Presentations at EASL

Data from four abstracts on telaprevir, which is in phase III development, will be presented in poster and oral presentations at EASL. Highlights include early results from VX06-950-107, an ongoing, open-label study to evaluate the antiviral response to treatment with telaprevir, combined with pegylated interferon alfa-2a (Peg-IFN) and ribavirin (RBV), in patients who have failed treatment with Peg-IFN/RBV in any of the three PROVE trials will be presented as a late-breaker poster. An interim analysis examined a small subset of patients that included non-responders and relapsers. These are the first data to be presented on the use of telaprevir in patients who have previously failed previous Peg-IFN/RBV therapy.

 

Further results from PROVE-1 (U.S.) and PROVE-2 (Europe), two randomised, placebo-controlled Phase II studies of telaprevir combined with Peg-IFN and with or without RBV in treatment-naďve patients with HCV genotype 1, will be presented in oral sessions on Thursday, 24 April and Friday, 25 April, respectively.

 

Telaprevir is currently being studied in Phase III clinical trials in treatment-naďve patients; a Phase III clinical trial in patients that have previously failed treatment will begin later this year. Tibotec has the right to develop and commercialise telaprevir in Europe, South America, the Middle East, Africa, India, Australia and New Zealand; Vertex will commercialise telaprevir in the U.S., Canada and Mexico.

 

TMC435350: First Results in Patients

In addition, data from a placebo controlled, double-blind Phase I study of TMC435350 will be presented in an oral session on Friday, 25 April. This study examined the safety, tolerability and pharmacokinetics of TMC435350 in healthy volunteers and also examined antiviral activity of the drug in a small number of HCV patients who had previously failed treatment. These are the first data to be presented on the use of TMC435350 in hepatitis C patients.

 

Tibotec and Medivir discovered TMC435350 through a drug discovery collaboration. Tibotec has the right to commercialise the compound throughout the world, excluding the Nordic countries. A Phase IIa proof-of-concept trial is ongoing in Europe and is currently recruiting patients.

 

About Tibotec

Tibotec BVBA, is a pharmaceutical research and development company. The Company's main research and development facilities are in Mechelen, Belgium with offices in Yardley, PA and Cork, Ireland. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS and hepatitis C drugs, and anti-infectives for diseases of high unmet medical need. http://www.tibotec.com

 

Three Studies Presented at 43rd EASL Strongly Indicate Better Efficacy for PEGASYS in Curing Hepatitis C

http://www.presseportal.de

 

Basel, Switzerland (ots/PRNewswire) - - Roche Also Provides Comment on Results of "IDEAL" Trial

 

Roche today announced that compelling new data from three studies indicate that chronic hepatitis C patients who received PEGASYS(R) (peginterferon alfa-2a) plus COPEGUS(R) (ribavirin) had a greater chance of being cured of their disease than those who received combination therapy with another pegylated interferon and ribavirin. Results from the studies were presented this week at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) in Milan, Italy.

 

Ascione, et al: A Prospective, Randomised, Investigator-Initiated Head-to-Head Trial

Results of this independently-conducted study(1) were presented by Professor Antonio Ascione, Director of the Department of Gastroenterology Liver Unit at Cardarelli Hospital in Naples, Italy, in the oral late-breaker session at EASL. It is a prospective, randomised, investigator-initiated head-to-head trial designed to directly compare Pegasys with peginterferon alfa-2b, each in combination with ribavirin. Enrolling 320 patients in Italy, the study randomised patients to receive either Pegasys 180 mcg/week or peginterferon alfa-2b 1.5 mcg/kg/week. Importantly, patients received equivalent starting doses of ribavirin (either 1,000 or 1,200 mg ribavirin per day based on body weight), and the process for ribavirin dose reduction was the same for all patients.

 

The results showed that 68.7% of patients on Pegasys achieved a cure, compared to only 54.4% of patients on peginterferon alfa-2b (p=0.008). Furthermore, in genotypes 1 and 4 - the most difficult-to-treat patient group - Pegasys achieved a cure in 54.8% of patients, compared to only 39.8% on peginterferon alfa-2b (p=0.04). Side effects were similar, although there were more withdrawals for side effects in the peginterferon alfa-2b group.

 

T. Witthoeft, et al: Hepatitis C Treatment in Real-Life PRACTICE in Germany

Another study presented at EASL, called PRACTICE, analysed the response of 3,470 patients to hepatitis C treatment between 2000 and 2007 in 23 German treatment centres with a high volume of patients(2). Patients were matched by key baseline characteristics, as well as by those who received a similar cumulative ribavirin dose. Among these matched pairs, significantly more patients treated with Pegasys plus Copegus achieved a cure compared to those treated with peginterferon alfa-2b and ribavirin (59.3% vs. 53.0% (p = 0.008)).

 

Craxi, et al: PROBE Compares the Pegylated Interferons

PROBE, an observational study, was designed to prospectively evaluate the efficacy of the pegylated interferons in real-life practice(3). The study enrolled 1,351 patients with genotype 1 virus at 167 treatment centres in Italy. Again, the trial found a greater chance of a cure in patients treated with Pegasys combination therapy compared to those treated with peginterferon alfa-2b combination therapy (41% versus 34%, respectively (p=0.004)).

 

"We are pleased that three separate studies presented at EASL all indicate that Pegasys provided patients with a better chance for a cure. These results will help physicians and patients make an informed choice of treatment for chronic hepatitis C. In fact, in all the major markets, an increasing proportion of physicians and patients have selected Pegasys for their therapy in the last several months," said Dr Ueli Fankhauser, global leader for Pegasys at Roche. "We are committed to further advancing the treatment of hepatitis C. Reflecting Roche's leadership in this area, our comprehensive clinical trials programme aims to optimise treatment with Pegasys and Copegus in the hope of bringing treatment success to even more patients."

 

Roche Comments on Schering-Plough "IDEAL" Study

Roche reiterated its position on the Schering-Plough sponsored trial called "IDEAL," results of which were also presented at EASL. Clear biases(4) in the design of this study prevent any direct comparison of the pegylated interferons. These biases include:

 

  • different blinding for the Pegasys arm,
  • different ribavirin starting doses,
  • a different ribavirin dose reduction protocol, and
  • unequal thresholds for the use of erythropoietin-stimulating agents.

 

Despite these biases, it is interesting to note that significantly more patients in the Pegasys arm had an undetectable viral load while on treatment ("end of treatment" response)(5). This is a promising finding, given that the likelihood for a cure in these patients is even higher when modern treatment principles, such as extending the treatment period beyond 48 weeks, are applied. In addition, the study failed to show a benefit for weight-based dosing of peginterferon alfa-2b (which requires dose adjustments based on a patient's body weight) vs. Pegasys, which is given as a fixed dose regardless of a patient's body weight.

 

Roche's R1626, First-in-Class Hepatitis C Polymerase Inhibitor, Demonstrates Impressive End-of-Treatment Response in Phase IIa Study

http://www.finanznachrichten.de

Basel, Switzerland (ots/PRNewswire) -

 

- R1626 Also Shows a High Barrier to the Development of Resistance

 

Roche's investigational treatment for hepatitis C, R1626, has shown an impressive end-of-treatment response rate when given in combination with PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin).

 

After 4 weeks of treatment with this triple combination, followed by 44 weeks of Pegasys and Copegus, levels of the hepatitis C virus (HCV) were undetectable in 84% of patients infected with genotype 1 virus. This was higher than in patients treated with Pegasys and Copegus alone for the entire 48-week treatment period (65%).(1) These new data were presented in a late-breaker oral session at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), being held in Milan, Italy.

 

Discovered and developed at Roche, (News/Aktienkurs) R1626 is a potent polymerase inhibitor which belongs to a new generation of treatments that directly inhibit replication of HCV. It is the most advanced polymerase inhibitor in development.

 

"These results demonstrate that R1626 holds significant promise to potentially increase the number of hepatitis C patients who can be successfully treated. It is particularly interesting that R1626, a polymerase inhibitor, is demonstrating a higher end-of-treatment response rate than current HCV protease inhibitors in development, together with a high barrier to the development of resistance," said Dr David Nelson, Director of Hepatology and Liver Transplantation at the University of Florida, Gainesville, Florida, USA. "Since most patients responded very early in treatment with R1626, we expect excellent SVR rates that improve significantly on those achieved with the current standard of care. I look forward to SVR data from this Phase IIa study, and to results of the ongoing Phase IIb study."

 

Patients in this Phase IIa study will be followed for an additional 24 weeks with no treatment to determine the rate of sustained virological response (SVR), indicating a cure.

 

Rapid development of R1626 - a Large Phase IIb Study is Now Fully Enrolled

 

A large Phase IIb study with R1626 was initiated in November 2007 to define the optimal dose of R1626, in combination with Pegasys and Copegus. This Phase IIb trial, called POLI 1, is now fully enrolled with approximately 500 patients.

 

More About the Phase IIa Study and End-of-Treatment Results Presented at EASL

The Phase IIa study is a multicenter trial that enrolled 104 patients with genotype 1 HCV, who had not previously received treatment. Its primary endpoint was to evaluate the 4-week efficacy and safety of combining R1626 with Pegasys alone or with Pegasys plus Copegus, in comparison to a current HCV standard of care, Pegasys plus Copegus.

 

Patients were randomised into the following treatment groups:

 

  • Group A: R1626 1,500 mg twice a day plus Pegasys 180 mcg weekly for 4 weeks
  • Group B: R1626 3,000 mg twice a day plus Pegasys 180 mcg weekly for 4 weeks
  • Group C: R1626 1,500 mg twice a day plus Pegasys 180 mcg weekly plus Copegus 1,000/1,200 mg daily for 4 weeks
  • Group D (standard of care group): Pegasys 180 mcg weekly plus Copegus 1,000/1,200 mg daily for 4 weeks

 

Following the 4 weeks of treatment in this study, all patients received Pegasys 180 mcg weekly plus Copegus 1,000/1,200 mg daily for an additional 44 weeks to complete the 48-week trial.

 

The study found(1):

 

  • Data collected at 4 weeks showed that patients receiving the triple combination (Group C) had a mean decrease in viral load of 5.2 log10 from baseline, indicating a robust and rapid virological response
  • At week 48, HCV was undetectable in 84% of patients receiving the triple combination R1626 1,500 mg BID + Pegasys + Copegus, compared with 65% of patients treated with Pegasys and Copegus alone
  • A higher incidence of grade 4 neutropaenia was reported in the R1626 treatment arms during the 4-week treatment period; however, after stopping treatment with R1626, absolute neutrophil counts returned to the levels typically seen with patients taking standard of care alone

 

R1626 - a High Barrier to the Development of Resistance

In a separate oral presentation at EASL, it was reported that R1626 continues to present a high barrier to the development of viral resistance. Resistance is a serious concern in hepatitis C treatment, as resistant viruses have emerged in patients early on in treatment with protease inhibitors. Resistance to R1626 has not been yet been identified, after either 2 weeks of R1626 monotherapy, or after 4 weeks in patients treated with R1626 in combination therapy.(2)

 

Vertex Announces Positive Interim Results with Telaprevir-based . Therapy in Genotype 1 Chronic Hepatitis C Patients who Failed to Achieve S SVR with a previous pegylated interferon and ribavirin treatment regimen.

http://www.infobolsa.es

 

In a late-breaker poster presentation at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), researchers today will present data from an interim analysis of telaprevir (VX-950) in combination with pegylated interferon and ribavirin in genotype 1 chronic hepatitis C patients who failed to achieve SVR with a previous pegylated interferon and ribavirin treatment regimen.

 

The interim results are from the 107 study, an ongoing, open-label study which was designed to provide access to telaprevir in patients who met on-treatment criteria for null or partial response, or relapsed after the completion of 48 weeks of pegylated-interferon (peg-IFN) and ribavirin (RBV), in the control arms of the telaprevir Phase 2b PROVE studies.

 

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) is developing telaprevir in collaboration with Tibotec.

 

In the interim analysis, patients treated with telaprevir in combination with peg-IFN and RBV demonstrated a high rate of viral response at week 4 (49 of 60 patients achieved HCV RNA <25 IU/mL).

 

This response appears to have been maintained, with no viral breakthrough observed to date in the 36 patients who have completed 4 weeks of treatment and continued out to 8 weeks and in the 16 of those patients who have continued out to 12 weeks of treatment.

 

"While early, these results are very promising.

 

Patients who have not achieved SVR with prior treatment represent the largest unmet medical need in hepatitis C, as typically only 10% to 15% of those re-treated with current therapies achieve sustained virologic responses.

 

The fact that the most difficult-to-treat patients showed such a profound early response is very encouraging," said Fred Poordad, M.D., study author of the PROVE 1 and 107 studies, and Chief of Hepatology at the Cedars-Sinai Center for Liver Disease and Transplantation.

 

The results will be presented in a late-breaker poster titled, "A Study of Telaprevir (TVR) with Peginterferon alfa-2A (P) and Ribavirin (R) in Subjects with Well-documented Prior P/R Null Response, Non-Response or Relapse: Preliminary Results" starting today.

 

Interim Data Analysis Summary - 107 Study

The 107 study results presented at EASL represent an interim analysis for patients who received telaprevir-based therapy.

 

Patients could enroll in the 107 study if they did not achieve SVR in the control arms of the Phase 2b telaprevir studies - PROVE 1, 2 and 3.

 

These patients were followed closely in the PROVE studies and can be well-characterized as null responders, partial responders or relapsers to standard treatment.

 

Null responders are defined as patients who had less than a 1 log(10) decrease in HCV RNA at week four or less than a 2 log(10) decrease in HCV RNA at week 12.

 

Partial responders are defined as patients who had a greater than 2 log(10) decrease in HCV RNA at week 12, but had detectable HCV RNA at week 24.

 

Relapsers are defined as patients who had undetectable HCV RNA at the end of treatment but reverted to detectable levels of HCV RNA after stopping treatment.

 

The results include data from all enrolled patients in study 107 who received at least one dose of telaprevir-based treatment and who completed the week 4 assessment.

 

At the time of analysis, 72 patients had received at least one dose of study drug and 60 patients had completed week 4.

 

Patients continued treatment at week 4 and 12 if they did not meet the stopping rule criteria, defined as HCV RNA >25 IU/mL (Roche Taqman assay, version 2.0) at either of those time points.

 

Nine patients discontinued all study treatment prior to week 12, including 5 patients who met the week 4 stopping rule, 2 patients who experienced breakthrough (both at week 2), 1 patient who discontinued due to an adverse event, and 1 patient who discontinued due to an adverse event and also met the week 4 stopping rule.

 

A high proportion of patients, regardless of the patient s degree of non-response to prior treatment, achieved HCV RNA <25 IU/mL at week four of treatment, and available data as of the interim analysis indicate that in patients who continued past week four, response has been maintained through week 12.

 

Week 4, 8 and 12 on-treatment antiviral responses are summarized in the table “-0- *T Prior Virologic Response in Interim HCV RNA Results in Patients Phase 2 control arm Reaching Week 4, 8 and 12 Assessments studies” 

 

Interim Results From Boceprevir Phase II Study In Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL

http://www.medicalnewstoday.com

 

Schering-Plough Corporation (NYSE: SGP) reported that results from a planned interim analysis of an ongoing Phase II study of boceprevir, its investigational oral hepatitis C protease inhibitor, in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL). The ongoing study evaluates boceprevir in 28-week and 48-week treatment regimens.

 

In a 28-week treatment regimen in which patients received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) prior to the addition of boceprevir (800 mg TID), the rate of sustained virological response at 12 weeks after the end of treatment (SVR 12) was 57 percent (ITT).(1-3) Importantly, this treatment regimen provided an indication of early predictability of response, with patients who had undetectable virus (HCV-RNA) in plasma after 4 weeks of boceprevir treatment achieving an SVR 12 rate of 86 percent.

 

"These interim results are very encouraging, especially given the response seen with a shorter course of therapy in a difficult-to-treat patient population," said principal investigator Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, who presented the data. "Boceprevir has been well tolerated by patients in this study, including in the longer duration treatment arms, and we look forward to further results from this ongoing study."

 

Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represent 16 percent of the patients enrolled and 7 percent of patients in the study are cirrhotic.

 

In the ongoing study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) is being evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment); boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks (triple combination); and boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily) for 48 weeks, compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). The primary endpoint of the study is sustained virologic response after 24 weeks of follow up.

 

During a late-breaker oral presentation at EASL, Dr. Kwo presented interim results for the two 28-week boceprevir arms of the study. For patients receiving 4 weeks of PEGINTRON and REBETOL therapy prior to the addition of boceprevir, SVR 12 was 57 percent (59/103), compared to 55 percent (59/107) for patients in the boceprevir triple combination arm. For patients in these two boceprevir arms who had undetectable virus (HCV-RNA) after 4 weeks of boceprevir treatment (RVR), the SVR 12 rates were 86 percent (53/62) and 74 percent (31/42), respectively. SVR 12 rates are not yet available for patients in the 48-week boceprevir arms or the 48-week control arm, as treatment of these patients is ongoing.

 

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. No increase in skin adverse events (rash or pruritus) beyond what was seen in the PEGINTRON and REBETOL control arm was observed. Treatment discontinuations due to adverse events were between 11 and 15 percent for patients in the boceprevir arms, compared to 8 percent for the control arm.

 

Early response rates at week 4 (RVR) and week 12 (EVR) of boceprevir treatment were increased for patients who received 4 weeks of PEGINTRON and REBETOL therapy prior to the administration of boceprevir (62 and 79 percent, respectively), compared to patients in the triple combination (38 and 69 percent) and control (8 and 34 percent) arms, respectively. In the 28-week boceprevir arms, these patients also had a reduction in viral breakthrough compared to patients in the triple combination arm (4 vs. 7 percent, respectively).

 

"The results seen with this novel treatment paradigm will influence the design of our future clinical studies, as we plan to consider RVR at week 4 of boceprevir treatment as the criterion for determining which patients can receive a shorter course of boceprevir therapy and which patients should continue treatment for 48 weeks," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "Additionally, this strategy has the potential to reduce the likelihood of the development of resistance by identifying patients who are responders to interferon and ribavirin prior to their receiving a protease inhibitor."

 

The rationale for this novel treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, so patients have the protease inhibitor added at a time when the backbone drug levels have been optimized. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral, potentially reducing the likelihood for the development of resistance.

 

The HCV SPRINT-1 study is currently ongoing at sites across the United States, Canada and Europe. Final results from the study are anticipated to be available in early 2009, and will be submitted for presentation at an appropriate medical meeting.

 

Gilead Announces 72-Week Data From Two Pivotal Phase III Studies Evaluating Viread(R) for the Treatment of Chronic Hepatitis B

http://www.infobolsa.es

 

Resistance surveillance through week 72 did not detect any tenofovir-associated mutations.

 

Two patients exhibited loss of viral response as defined by study investigators with documented non-adherence and were evaluated via genotypic analysis.

 

Neither developed mutations associated with Viread resistance.

 

Study 103 Study 103 is a multi-center, randomized, double-blind Phase III clinical trial evaluating the efficacy, safety and tolerability of Viread among treatment-naive patients with HBeAg-positive chronic hepatitis B.

 

Two hundred sixty-six patients were originally randomized in a 2:1 ratio to receive either Viread (300 mg once daily; n=176) or Hepsera (10 mg once daily; n=90).

 

Baseline characteristics were similar between patients in both study arms.

 

As with Study 102, after the completion of 48 weeks of randomized blinded therapy, all eligible patients were offered open-label Viread monotherapy.

 

At week 72, 79 percent of patients who were originally randomized to receive Viread had a virologic response below 400 copies/mL.

 

Among Hepsera-treated patients who switched to Viread after Week 48, 76 percent achieved HBV DNA below 400 copies/mL by week 72.

 

Through week 72, viral suppression was maintained among all patients who switched to Viread and who were previously virologically controlled with Hepsera (n=12).

 

Additionally, rapid viral suppression to less than 400 copies/mL was achieved by week 72 in 78 percent of viremic Hepsera-treated patients who switched to Viread after week 48.

At week 72, normal ALT levels were observed in 77 percent of patients who were originally randomized to receive Viread and 61 percent of Hepsera-treated patients who switched to Viread.

 

Among patients for whom seroconversion data was available through week 64, 26 percent of patients who were originally randomized to receive Viread "e" antigen seroconverted, compared to 21 percent of Hepsera-treated patients who switched to Viread.

 

Seroconversion is defined as both the disappearance of the hepatitis B "e" antigen (HBe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for this antigen (HBe-antibody positive).

 

In addition, 5 percent of patients who were originally randomized to receive Viread compared to zero percent of Hepsera-treated patients who switched to Viread after week 48 experienced "s" antigen (HBsAg) loss (p=0.004), which can indicate that a patient has cleared chronic hepatitis B infection.

 

As with Study 102, Viread was generally well tolerated.

 

At week 72, treatment-related serious adverse events occurred in 4 percent of patients who were originally randomized to receive Viread and 7 percent of Hepsera-treated patients.

 

The incidence of Grade 4 laboratory abnormalities was comparable in each arm (12 percent versus 11 percent).

 

Grade 3 laboratory abnormalities, excluding ALT elevations, were 18 and 10 percent, respectively.

 

Grade 3 ALT elevations were 15 and 10 percent, respectively, in the Viread and Hepsera arms.

 

No patient had a confirmed creatinine clearance of less than 50 mL/minute.

 

The most common adverse reactions among patients receiving Viread for chronic hepatitis B in Studies 102 and 103 were headache, diarrhea, vomiting, abdominal pain, nausea, abdominal distension, flatulence, ALT increase and fatigue.

 

In terms of resistance surveillance, between weeks 48 and 72 no patients experienced a loss of virologic response.

 

Additional Oral Presentations at EASL Three additional oral presentations, one of which features the first data to be presented from Study 106, will be highlighted at EASL.

 

Study 106 is an ongoing, randomized, double-blind Phase II study of individuals with chronic hepatitis B infection randomized in a 1:1 ratio 

 

Clinical Update - Debio 025 in Hepatitis C

http://www.prnewswire.com

 

Presentation of Phase IIa Efficacy Results

 

LAUSANNE, Switzerland, April 28 /PRNewswire/ -- Debiopharm Group (Debiopharm), a global independent biopharmaceutical development specialist  focusing on serious medical conditions, particularly oncology, presented positive efficacy results of a phase IIa study with Debio 025, a selective cyclophilin (Cyp) inhibitor with a potent in-vitro and in-vivo anti-hepatitis C (HCV) effect. Data indicates that Debio 025 shows an important additive anti-HCV effect when co-administered with pegylated Interferon (Peg-IFN) alpha-2a to treatment- naive HCV patients. Debiopharm presented these findings at the 43rd Annual Meeting of the European Association for the Study of the Liver, in Milan, Italy.

 

The double-blind, placebo-controlled study investigated different dose regimens of Debio 025 in combination with alpha-2a Peg-IFN 180 Mug/week in treatment naive chronic HCV mono-infected patients. Ninety patients were randomised to receive either of the following treatment regimens during 29 days: Peg-IFN with placebo; Peg-IFN with Debio 025 200 mg/day; Peg-IFN with Debio 025 600 mg/day; Peg-IFN with Debio 025 1000 mg/day; and Debio 025 1000 mg/day.

 

In patients with genotypes 1 and 4, at day 29, the HCV-RNA reduction was -4.6 log10 IU/mL in the Peg-IFN with Debio 025 600 mg/day arm, and -4.8 log10 IU/mL in the Debio 025 1000 mg/day arm. This was significantly different (p< 0.05) from the Peg-IFN with placebo, as well as the Debio 025 1000 mg/day monotherapy arms, in which the reduction in viral load was respectively -2.49 and -2.20. In these two arms, at day 29, the proportion of subjects with undetectable viral load was 25%. This number increased to 66% in the Peg-IFN with Debio 025 1000 mg/day group.

 

"To obtain these exciting results after an administration period of only one month is promising and demonstrates that Debio 025 will be a breakthrough in the treatment of HCV infections," said Kamel Besseghir, CEO of Debiopharm S.A. "This unique mechanism of action is the first alternative treatment to classic HCV therapies."

 

Debio 025

Debio 025 is a synthetic first-in-class Cyp inhibitor, being tested in humans as a potential anti-HCV drug. Debio 025 binds strongly to Cyp, host cell proteins thought to confer a replication advantage to HCV. Its potent inhibitory activity on the HCV replication was shown in preclinical studies.

 

Previous results of a phase Ib study demonstrate that Debio 025 monotherapy for 15 days induced a strong anti-HCV effect (3.6 log10 reduction) in HIV-1/HCV co-infected patients. (Hepatology, Vol. 47, No 3, 2008, Flisiak et al. "The Cyclophilin Inhibitor Debio-025 Shows Potent Anti-Hepatitis C Effect in Patients Coinfected with Hepatitis C and Human Immunodeficiency Virus)."

 

About Debiopharm Group

Debiopharm Group is a global biopharmaceutical development specialist that in-licenses promising biologics and small molecule drug candidates. Debiopharm develops its products for global registration and maximum commercial potential for out-licensing to pharmaceutical partners for sales and marketing. Debiopharm independently funds the worldwide development of all of its products while providing expertise in pre-clinical and clinical trials, manufacturing, drug delivery and formulation, and regulatory affairs.

 

Founded in 1979 and headquartered in Lausanne, Switzerland, Debiopharm has developed three products with global combined sales in excess of US$2.65 billion in 2007.

 

For more information on Debiopharm Group, please visit: http://www.debiopharm.com.

 

Baraclude (Entecavir) Treatment Resulted In Greater Viral Load Suppression Compared to Adefovir at 96 Weeks In Antiviral-Naive Adult Chronic Hepatitis B E-Antigen Positive Patients

http://pharmalive.com

 

MILAN, Italy, April 26, 2008 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company today announced new data from the E.A.R.L.Y. study (ETV-079), in which treatment of antiviral-naive adult chronic hepatitis B patients with Baraclude(R) (entecavir) resulted in greater long-term viral load reduction than adefovir at 96 weeks -- consistent with earlier 12-week results (primary endpoint). Suppression of viral load to undetectable levels is a measure of antiviral treatment response and is an important goal of chronic hepatitis B treatment. These data were presented today in Milan, Italy, at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

 

The E.A.R.L.Y. study is an open-label, randomized, viral kinetics study of 69 antiviral-naive chronic hepatitis B e-antigen (HBeAg) positive patients, comparing the antiviral activity of BARACLUDE and adefovir. All patients in this study had a high viral load at study entry.(1) Of the 49 patients who remained in the study at 96 weeks, 79 percent (n=23/29) of BARACLUDE-treated patients and 50 percent (n=10/20) of adefovir-treated patients achieved undetectable viral load.(2) The mean reduction in viral load from baseline in patients treated with BARACLUDE was -7.82 log(10) copies/mL and was -5.96 log(10) copies/mL in patients treated with adefovir at week 96.

 

"BARACLUDE maintains considerable antiviral efficacy through two years of treatment in this analysis," said Nancy Leung, M.D., of the Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China. "This is important information for health care providers to consider when evaluating initial treatment options to suppress viral load in antiviral-naive chronic hepatitis B patients."

 

The safety profile was comparable between the treatment groups through 96 weeks. Three percent of patients receiving BARACLUDE(R) (entecavir) (n=1) and 12 percent of patients receiving adefovir (n=5) experienced a serious adverse event. No deaths were observed in either treatment group. The most common adverse events occurring in greater than 10 percent of patients in either treatment group were headache, nasopharyngitis, upper respiratory tract infection, influenza, pyrexia, urinary tract infection, cough, back pain, and diarrhea.

 

Data Results

By week 96, 22 of the 69 enrolled patients had discontinued the study. Of these, two patients receiving adefovir discontinued due to investigator-determined lack of treatment efficacy between the beginning of year two dosing and the 96-week analysis. The 96-week data reported below represent the results of the 49 patients who entered year two dosing (29 BARACLUDE-treated patients and 20 adefovir-treated patients), using the non-completer = failure (NC=F) method of analysis.

 

Week 96

·        BARACLUDE-treated patients achieved a mean change in viral load of -7.82 log(10) copies/mL from baseline, and adefovir-treated patients achieved a mean change of -5.96 log(10) copies/mL.

·        79 percent (n=23/29) of BARACLUDE-treated patients and 50 percent (n=10/20) of adefovir-treated patients had undetectable viral load (HBV DNA less than 300 copies/mL, measured by the polymerase chain reaction or PCR assay).

·        No BARACLUDE-treated patient (n=0/29) and 35 percent (n=7/20) of adefovir-treated patients had viral load greater than or equal to 10^5 copies/mL.

·        97 percent (n=28/29) of BARACLUDE patients achieved ALT normalization (ALT of less than or equal one time the upper limit of normal) compared with 85 percent (n=17/20) of adefovir-treated patients.

·        24 percent (n=7/29) BARACLUDE-treated patients achieved Hbe seroconversion compared with 25 percent (n=5/20) adefovir-treated patients.

·        Six BARACLUDE(R) (entecavir)-treated patients and 16 adefovir-treated patients discontinued therapy prior to week 96.

·        No BARACLUDE-treated patients and one adefovir-treated patient discontinued due to adverse events.

·        No BARACLUDE-treated patients and six adefovir-treated patients discontinued due to investigator-determined treatment failure or lack of efficacy.

·        Three BARACLUDE-treated patients and four adefovir-treated patients met the treatment response criteria at 52 weeks and entered a 24- or 48-week off-treatment follow-up monitoring phase.

·        Two BARACLUDE-treated patients and one adefovir-treated patient were lost to follow-up, one BARACLUDE-treated patient was non-compliant, two adefovir-treated patients withdrew consent, one adefovir-treated patient became pregnant, and one adefovir-randomized patient was treated with BARACLUDE.

 

Week 12 (primary endpoint)

·        BARACLUDE-treated patients achieved a mean change in viral load of -6.23 log(10) copies/mL from baseline, compared to adefovir-treated patients who achieved a mean change of -4.42 log(10) copies/mL (p < 0.0001).

·        12 percent of BARACLUDE-treated patients and 9 percent of adefovir-treated patients had undetectable viral load (HBV DNA <300 copies/mL).

 

Additional Cumulative Safety Results of the E.A.R.L.Y. Study at 96 Weeks

·        83 percent of patients in the BARACLUDE arm (n=30) and 82 percent of patients in the adefovir arm (n=27) experienced any adverse event.

·        Eight percent of patients receiving BARACLUDE (n=3) and 15 percent of patients receiving adefovir (n=5) experienced any Grade 3-4 adverse event.

·        Three percent of patients receiving BARACLUDE (n=1) and 12 percent of patients receiving adefovir (n=5) experienced a serious adverse event.

·        No deaths were observed in either treatment group.

·        No patients in the BARACLUDE arm and one patient in the adefovir arm experienced an ALT flare (defined as ALT greater than two times baseline and greater than 10 times the upper limit of normal).

 

About the Study

The E.A.R.L.Y. study (ETV-079) is a randomized, open-label, comparative viral kinetics study of antiviral-naive chronic HBeAg-positive patients evaluating antiviral activity as measured by mean reduction in viral load, or levels of hepatitis B virus (HBV DNA) in the blood. HBeAg or e-antigen, is a viral protein associated with hepatitis B infections, and is found in the blood only when there is virus present.

 

The primary endpoint for the study was mean reduction in HBV DNA levels at week 12. The secondary endpoints included the mean change in viral load from baseline through week 96, the proportion of patients in each treatment group who achieved ALT normalization, HBeAg loss and HBe seroconversion, and safety.

 

Sixty-nine patients were randomized in the study and of these, 65 completed the first 12 weeks. Patients in this study received either 0.5 mg of BARACLUDE(R) (entecavir) once daily (n=33) or 10 mg of adefovir once daily (n=32) for a minimum of 52 weeks. Patients in the BARACLUDE treatment group had a mean baseline viral load of 10.26 log(10) copies/mL. Patients in the adefovir treatment group had a mean baseline viral load of 9.88 log(10) copies/mL.

 

According to study protocol, patients who achieved a treatment response at 52 weeks discontinued treatment and entered a follow-up monitoring phase. Three BARACLUDE-treated patients and four adefovir-treated patients met this criterion and entered the follow-up monitoring phase lasting up to 48 weeks. Patients who did not achieve a treatment response at 52 weeks continued on study to 96 weeks. Treatment response in this study is defined as HBeAg seroconversion and viral load less than 104 copies/mL for 24 weeks, with undetectable viral load at the end of the 24-week period.

 

Nitazoxanide Demonstrates Activity in Treatment-Naive Patients With Hepatitis C Virus Genotype 4: Presented at EASL

http://www.docguide.com

By Emma Hitt, PhD

 

MILAN, Italy -- April 29, 2008 -- Nitazoxanide significantly improves response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic hepatitis C virus genotype 4 (HCV-4), according to new research findings presented here at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

 

Jean-Francois Rossignol, MD, Research Scientist, and Cofounder, Romark Institute For Medical Research, Tampa, Florida, reported the results of a randomised trial of nitazoxanide, an oral agent that targets host-cell interactions with HCV. Dr. Rossignol and colleagues sought to evaluate the antiviral activity and safety of nitazoxanide in combination with PEG-IFN alfa-2a, with or without ribavirin.

 

A total of 120 patients with chronic HCV-4 were sequentially randomised to 1 of 3 treatment arms. The first arm was a standard-of-care arm: PEG-IFN alfa-2a plus ribavirin (RBV) for 48 weeks. The second arm was nitazoxanide for 12 weeks followed by nitazoxanide plus PEG-IFN alfa-2a for 36 weeks. The third arm was a triple therapy consisting of nitazoxanide for 12 weeks followed by nitazoxanide combined with PEG-IFN alfa-2a plus RBV for 36 weeks.

 

PEG-IFN alfa-2a was injected by clinical investigators at 180 mcg/kg/week while ribavirin was dosed at 1000 to 1200 mg/day. Nitazoxanide was administered at 500 mg twice daily with food.

 

Patients were previously untreated, with the exception of 12 interferon-experienced patients included in each of the nitazoxanide-containing arms.

 

During the monotherapy lead-in phase with nitazoxanide, a modest (0.25 log10) but statistically significant decrease in HCV ribonucleic acid (RNA) from baseline to week 12 was observed (P = .0032). Out of 76 patients, 5 had a drop in HCV RNA of greater than 1 log10 from baseline to week 12; and 1 patient had undetectable HCV RNA, with a 5.4 log10 decline in HCV RNA and normalised alanine aminotransferase (ALT) test results at week 12. There was no significant change in overall ALT measurements during the lead-in period.

 

Among the interferon-naive patients (n = 96), the patients receiving the triple regimen (nitazoxanide plus PEG-IFN plus RBV) achieved a higher sustained viral response (SVR) than the patients receiving the standard of care (79% vs 50%; P = .023). In the nitazoxanide arm without RBV, the SVR was 61%. The rapid viral response (RVR) was also higher in patients receiving the triple therapy compared with those receiving the standard of care (64% vs 38%; P = .048).

 

In the interferon-experienced patients (n = 24), no efficacy differences were observed between the 2 nitazoxanide-containing arms (not compared with standard of care).

 

"Adverse events in the overall population were characteristic of those typically observed with pegylated interferon and ribavirin, with no additional effects resulting from nitazoxanide," Dr. Rossignol noted here on April 25. "Additional clinical trials of nitazoxanide in interferon-naive patients and nonresponders to pegylated interferon plus ribavirin have been initiated in patients with HCV genotype 1 in the United States and Europe."

 

Nitazoxanide was initially developed as an antiprotozoal, antiviral, and antibacterial agent, and is approved for the treatment of diarrhoea caused by Cryptosporidium and Giardia in children. Nitazoxanide has since shown activity against HCV and hepatitis B virus.

 

[Presentation title: Randomized Controlled Trial of Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and Peginterferon-Ribavirin in the Treatment of Patients With Chronic Hepatitis C Genotype 4. Abstract 68]

 

Idenix Pharmaceuticals Presents Positive Preclinical Data on HCV Programs at The Annual Meeting of The European Association for the Study of the Liver (EASL)

http://www.therapeuticsdaily.com

 

CAMBRIDGE, Mass., and MILAN, Italy, April 23, 2008 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. , a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases, today announced preclinical data from the company's polymerase and protease inhibitor programs for the treatment of hepatitis C. These data are being presented at the Annual Meeting of the European Association for the Study of the Liver (EASL) being held this week in Milan, Italy.

 

Second-Generation Nucleoside Polymerase Inhibitor Program

IDX184 is a nucleotide prodrug derived from Idenix's proprietary liver- targeting technology. Results from in vitro and in vivo preclinical studies confirm that this technology preferentially activates IDX184 in the liver, potentially enhancing the antiviral activity of the drug and limiting systemic side effects. In an HCV replicon model, IDX184 exhibited 10 times greater potency than the first-generation HCV nucleoside clinical drug candidates currently in development. In HCV genotype-1 infected chimpanzees, once-daily oral administration of 10 mg/kg of IDX184 resulted in a mean viral load reduction of 2.3 log10 (n=5) after four days of dosing. No toxicities, including gastrointestinal or hematological, or abnormal blood chemistry were observed at oral doses greater than or equal to 600 mg/kg/day in a supporting seven-day toxicology study in cynomolgus monkeys.

 

IDX184 demonstrated additive antiviral activity in the HCV replicon in combination with HCV protease inhibitors and interferon and synergistic activity in combination with ribavirin. IDX184 also remained fully active in vitro against HCV containing known protease and non-nucleoside inhibitor drug resistance mutations.

 

Data from this program are being presented by David Standring, Ph.D., executive vice president, biology, Idenix Pharmaceuticals, in an oral presentation session at 5:30 p.m. CET on Friday, April 25, 2008, and by Erika Cretton-Scott, Ph.D., director, preclinical pharmacology at Idenix Pharmaceuticals, in a poster session beginning on Thursday, April 24, 2008.

 

Novel Macrocyclic Protease Inhibitor Program

Based on two novel macrocyclic scaffolds, Idenix has discovered compounds that demonstrated potency with subnanomolar antiviral activity against the HCV genotype 1b NS3/4A protease target and single nanomolar activity in the HCV replicon. These compounds also displayed high selectivity in vitro with no inhibition of selected human cellular proteases. In vitro, the Idenix protease inhibitors exhibited antiviral activity against certain HCV resistant mutants associated with first-generation protease inhibitors currently in clinical development. Pharmacokinetic studies demonstrated adequate oral bioavailability and sustained liver concentrations suggesting the potential for once-daily or twice-daily dosing. Data from this program are being presented by Dr. Standring in an oral presentation session at 6:15 p.m. CET on Thursday, April 24, 2008.

 

"The preclinical profiles emerging in our HCV nucleoside and protease inhibitor programs are very encouraging when compared to first-generation drug candidates from both of these drug classes," said David Standring, Ph.D., executive vice president, biology, of Idenix. "We plan to have product candidates from both of these programs in clinical development within the next 12 months with the goal to evaluate our own novel combinations thereafter."

 

About Idenix

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis C virus and HIV. For further information about Idenix, please refer to www.idenix.com.