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AASLD 2008: Investigational HCV Protease Inhibitor BI 201335 Exhibits Promising Antiviral Activity

Given the limited efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection -- especially among patients with hard-to-treat HCV genotype 1 -- investigators have explored several small molecule agents (dubbed "STAT-C") that directly target various steps of the viral lifecycle. One such candidate, BI201335, is an HCV NS3 protease inhibitor being developed by Boehringer-Ingelheim. Two posters with results from a Phase 1b study of BI201335 were presented last week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

Treatment-naive Patients

Study 1220.2 is a multinational clinical trial evaluating the pharmacokinetics, safety, and antiviral activity of multiple ascending doses of BI201335 monotherapy for 14 days, followed by triple therapy with BI201335 + pegylated interferon + ribavirin for an additional 14 days.

The first analysis looked at 34 treatment-naive patients with genotype 1 chronic hepatitis C in the U.S., France, Germany, and Spain. Most participants (27) were men, all but 1 were white, the mean age was about 49 years, and Metavir fibrosis scores were 0-3.

Participants were randomly assigned to receive placebo or 1 of 4 doses of once-daily BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8). BI201335 was given as monotherapy for 14 days. Patients with less than a 1 log10 decrease in HCV RNA at day 10 had BI201335 discontinued after day 14. Those with at least a 1 log10 decrease at day 10 continued on BI201335, adding 180 mcg/week pegylated interferon alfa-2a (Pegasys) + weight-adjusted ribavirin from day 15 through Day 28.

Results

• A rapid decline in HCV viral load was observed in all patients, with maximal decline 2-4 days after starting BI201335.

• With the exception of 1 patient in the 20 mg group, all participants receiving BI201335 (96.2%) achieved > 2 log10 decline in HCV RNA during the monotherapy period.

• 100% of patients in the 48 mg, 120 mg, and 240 mg BI201335 dose groups achieved > 2.8 log10 drop in HCV viral load during the first few days of monotherapy.

• Median maximal reductions in viral load during the 14-day monotherapy period were 3.0 log10 in the 20 mg arm, 3.6 log10 in the 48 mg arm, 3.7 log10 in the 120 mg arm, and 4.2 log10 in the 240 mg arm, versus no significant change in the placebo group.

• A majority of patients in all dose groups experienced viral load rebound during the first 14 days of monotherapy.

• Population sequencing of the NS3/NS4A protease at baseline and after viral rebound revealed selection of HCV variants previously shown to confer resistance to BI201335 in vitro.

• BI201335 was generally well-tolerated, with no observed dose-dependent increases in adverse events (AEs).

• No patients discontinued treatment during the monotherapy period due to AEs.

• AEs observed while on combination therapy were typical for pegylated interferon + ribavirin.

• Changes in bilirubin were observed with increasing doses of BI 201335.

• One serious AE (asthenia, or muscle weakness) occurred in an individual in the 20 mg dose arm 6 days after starting pegylated interferon + ribavirin.

In conclusion, the investigators stated, "BI 201335 as monotherapy for 14 days followed by combination with [pegylated interferon + ribavirin] for [an] additional 14 days was well tolerated, and induced a strong and rapid antiviral response."

"The results support further study of BI201335 as a once-daily potent antiviral for treatment-naive HCV patients," they added.

Medizinische Hochschule Hannover Zentrum Innere Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie Salpetriere, Paris, France; California Pacific Medical Center Research Institute, San Francisco, CA; Charité Berlin Campus Virchow-Klinikum, Berlin, Germany; Hopital Hotel Dieu, Lyon, France; Central Texas Clinical Research, Austin, TX; Hopital Cochin, Paris, France; Boehringer Ingelheim Pharma, Ridgefield, CT; Hospital Universitario Puerta de Hierro, Madrid, Spain.

Treatment-experienced Patients

Study 1220.2 also included a cohort of 19 treatment-experienced patients with genotype 1 chronic hepatitis C who experienced confirmed virological failure (< 2 log reduction in HCV RNA from baseline) during or after previous combination therapy with approved doses of pegylated interferon + ribavirin. Here, too, a majority of participants were men, all were white, and the mean age was 49 years.

This part of the study was open-label, and all patients received BI201335 at doses of 48, 120, or 480 mg once-daily in combination with standard doses of Pegasys + ribavirin for 28 days (none received monotherapy or 20 mg BI201335).

Results

• Here again, a rapid dose-related decline in HCV RNA was observed in all patients.

• All participants treated with BI201335 + pegylated interferon + ribavirin achieved > 2 log10 decline in HCV viral load.

• Median maximal declines in HCV RNA during 28-day combination therapy were 4.8 log10 in the 48 mg arm, 5.2 log10 in the 120 mg arm, and 5.3 log10 in the 240 mg arm.

• 2 of 6 patients (33%) in the 48 mg group and 1 of 7 (14%) in the 120 mg group experienced virological rebound during the first 28 days of triple combination therapy.

• In these patients, sequencing of the NS3/4A protease revealed variants with known BI201335 resistance mutations.

• No viral rebound during treatment was seen in the 240 mg dose arm, and 5 of 6 patients (83%) in this group had HCV RNA < 25 IU/mL at day 28.

• Again, BI201335 was well-tolerated and no serious drug-related AEs were observed.

• AEs were typical for pegylated interferon + ribavirin.

• 1 participant discontinued treatment due to anxiety.

"BI201335 given once-daily in combination therapy with [pegylated interferon + ribavirin] for 28 days was well tolerated, and induced a strong and rapid antiviral response," the researchers concluded. "The results support further study of BI201335 as a potent protease inhibitor for [pegylated interferon + ribavirin] treatment-experienced HCV patients."

Medizinische Hochschule Hannover Zentrum Innere Medizin, Hannover, Germany; Hopital Saint Joseph, Marseille, France; Hopital Pitie Salpetriere, Paris, France; I. Med. Klinik und Poliklinik, Mainz, Germany; Universitätsklinikum Düsseldorf, Düsseldorf, Germany; Hopital Cochin, Paris, France; California Pacific Medical Center Research Institute, San Francisco, CA; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT.

11/11/08

References

MP Manns, M Bourliere, Y Benhamou, and others. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in treatment-naive patients with chronic hepatitis C genotype-1 infection given as monotherapy and in combination with Peginterferon alfa 2a (P) and Ribavirin (R). 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1849.

MP Manns, M Bourliere, Y Benhamou, and others. Safety and antiviral activity of BI201335, a new HCV NS3 protease inhibitor, in combination therapy with Peginterferon alfa 2a (P) and Ribavirin (R) for 28 days in P+R treatment-experienced patients with chronic hepatitis C genotype-1 infection. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1882.

24 Weeks of Pegylated Interferon plus Ribavirin May Be Sufficient for Selected Genotype 1/4 Chronic Hepatitis C Patients with Rapid Response

Given the side effects and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers continue to explore shorter treatment durations, especially for individuals who respond rapidly after starting therapy.

The current standard of care is 24 weeks of pegylated interferon plus ribavirin for chronic hepatitis C patients with HCV genotypes 2 or 3, while those with hard-to-treat genotypes 1 or 4 are treated for 48 weeks. Many experts recommend longer therapy for individuals with HIV-HCV coinfection.

In a study described in the August 2008 issue of Gastroenterology, Peter Ferenci and colleagues from Austria aimed to determine whether 24 weeks might be adequate for patients with HCV genotype 1 or 4 who achieve rapid virological response (RVR), or undetectable after 4 weeks of therapy.

The study initially included 516 genotype 1 or 4 patients treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin. Participants who did not achieve RVR (HCV RNA < 50 copies/mL) at week 4 were randomly assigned to receive 48 or 72 weeks of treatment (this part of the study was ongoing at the time of the report).

Among those who did achieve RVR, the investigators analyzed rates of sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completion of therapy.

Results

• 150 of the 516 patients (26%) achieved RVR.

• 143 of the 150 completed 24 weeks of treatment.

• The overall SVR rate in this subgroup was 80.4%:

• 78.8% for genotype 1;
• 86.7% for genotype 4.

• The following factors were predictive of RVR:

• younger age;
• lower body fat;
• low baseline HCV RNA (< 400,000 IU/mL);
• HCV genotype 4 rather than 1.

• However, once a person had achieved RVR, no baseline factors significantly predicted SVR.

• Treatment was well tolerated overall.

Based on these findings, the investigators concluded, "This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000-1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy."

Medical University, Vienna, Austria; Kaiser-Franz-Josef-Spital, Vienna, Austria; Wilhelminenspital, Vienna, Austria; Elisabethinen Hospital, Linz, Austria; Hospital Hietzing, Vienna, Austria; Medical University, Graz, Austria; Rudolfshospital, Vienna, Austria; LKH Hörgas-Enzenbach, Gratwein, Austria; Krankenhaus, Oberndorf, Austria; Roche Austria, Vienna, Austria.

10/14/08

Reference
P Ferenci, H Laferl, TM Scherzer, and others. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 135(2): 451-458. August 2008. (Abstract).

 

Active Injection Drug Use Does Not Impair Sustained Response to Hepatitis C Treatment in Adherent Patients

In the July 10 advance online edition of the Journal of Viral Hepatitis, Philip Bruggmann from the Association for Risk Reduction in the Use of Drugs in Zurich, Switzerland and colleagues reported results from a study of hepatitis C treatment in active drug users. As background, the authors noted that the medical literature provides no evidence for an unequivocal treatment deferral of active IDUs.Chronic hepatitis C virus (HCV) infection is common among injection drug users (IDUs) since the virus is readily transmitted through shared needles and other drug use equipment.

Combination Therapy with Investigational HCV Polymerase Inhibitor R7128 Produces Rapid Response in Patients with Genotype 2/3 HCV

Due to the limited efficacy and side effects of standard hepatitis C therapy using pegylated interferon (Pegasys or PegIntron) plus ribavirin, researchers are studying several oral agents that directly target various steps of the hepatitis C virus (HCV) lifecycle. One such agent, Pharmasset's R7128 (a prodrug of the nucleoside analog HCV polymerase inhibitor PSI-6130) is currently in Phase 1 clinical trials, in combination with Pegasys plus ribavirin. In August, the company reported preliminary data from a cohort of patients with hard-to-treat HCV genotype 1. This week, Pharmasset reported early results from a subgroup of participants with easier-to-treat genotypes 2 or 3.

DDW 2008: Active and Recovering Injection Drug Users Can Benefit from Hepatitis C Treatment if They Maintain Good Adherence

Because hepatitis C virus (HCV) can be transmitted via shared needles and other drug-injection equipment, a high proportion of active and former injection drug users (IDUs) have chronic hepatitis C.

Older Donor Liver Grafts May Be Suitable for Chronic Hepatitis C Patients Requiring Transplantation

Liver transplantation is the only effective treatment for end-stage liver failure due to chronic hepatitis C virus (HCV) infection, but the availability of the procedure is severely hampered by the shortage of donor organs. Surgeons have traditionally preferred to use livers from young donors, but increasing the age of acceptable donors could significantly expand the available liver supply. 

DDW 2008: Higher HBV DNA Levels Linked to Increased Risk of Liver Cirrhosis in People with Chronic Hepatitis B

 

In a study presented at the Digestive Disease Week 2008 conference last month in San Diego, researchers investigated the relationship between HBV DNA levels and progression to cirrhosis over a longer follow-up period.

Pharmasset Releases Preliminary Data from Phase 1 Study of Investigational HCV Polymerase Inhibitor R7128

Due to the limitations of standard hepatitis C treatment using pegylated interferon (Pegasys or PegIntron) plus ribavirin, researchers are studying several oral agents that directly target various steps of the hepatitis C virus (HCV) lifecycle.

These agents are in different stages of development. One that is further back in the pipeline is Pharmasset's R7128, a prodrug of the nucleoside analog HCV polymerase inhibitor PSI-6130, which is now in Phase 1 studies in patients with hard-to-treat HCV genotype 1.

Below is an edited excerpt from a Pharmasset press release announcing preliminary 4-week data from a new cohort added to the trial:

Pharmasset Reports Preliminary Results of a 4-week Combination Study of R7128 for the Treatment of Chronic Hepatitis C

Princeton, NJ -- August 05, 2008 -- Pharmasset, Inc. (Nasdaq: VRUS) announces the preliminary results of the third cohort of a 4-week Phase 1 clinical trial evaluating R7128 1000 mg twice daily (BID) in combination with the standard of care (SOC), Pegasys (pegylated interferon [alfa-2a]) plus Copegus (ribavirin), in 31 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 in collaboration with Roche.

As previously reported for Cohorts 1 and 2 of this study, R7128 has demonstrated potent short-term antiviral activity and was generally safe and well tolerated at doses of 500 mg and 1500 mg administered for 28 days in combination with SOC.

In Cohort 3, a new formulation of R7128 1000 mg BID was administered in combination with SOC. Of the 31 patients enrolled, 25 patients received R7128 1000mg BID and 6 received placebo. 88% (22 of 25) patients receiving R7128 1000mg BID with SOC for 4 weeks achieved undetectable HCV RNA levels (<15 IU/mL). This high rate of Rapid Virologic Response (RVR) compares favorably with the 85% RVR demonstrated earlier this year with R7128 1500 mg BID in combination with SOC. Based on these results, R7128 1000 mg BID will be among the doses carried forward into Phase 2b studies, which we expect to be submitted to the FDA this Fall.

The preliminary safety and tolerability of R7128 1000 mg BID with SOC was comparable to placebo with SOC in Cohort 3. One patient was discontinued from the study at day 7 for noncompliance with the protocol. One SAE [serious adverse event] of suicidal ideation was reported in a patient with significant psychiatric history (including prior suicide attempts) who was two weeks beyond the 28 days of dosing with R7128 and remaining on SOC.

Dr. Michelle Berrey, Pharmasset's Chief Medical Officer, stated, "This result indicates that it is unnecessary to carry the 1500 mg dose forward, since the 1000 mg dose may provide a greater margin of safety over longer treatment periods without sacrificing efficacy. Even at the dose of 500 mg, R7128 in combination with SOC has demonstrated a greater percentage of RVR compared to SOC alone, which provides flexibility in selecting doses for future clinical studies."

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 81 treatment-naive patients chronically infected with HCV genotype 1. The primary objective was to assess the safety, tolerability, pharmacokinetics and antiviral activity of R7128 in the clinically-relevant setting of combination therapy for chronic HCV infection. Cohort 1 administered R7128 500 mg BID, Cohort 2 administered R7128 1500 mg BID, and Cohort 3 administered an intermediate dose of 1000 mg BID, all given in combination with pegylated interferon and ribavirin for 28 days. All subjects then went on to receive a total of 48 weeks of the standard-of-care regimen. In Cohort 4, Patients with HCV genotypes 2 and 3 who did not achieve a SVR with previous interferon-based therapy were administered R7128 1500 mg BID in combination with SOC for 4 weeks, and subsequently treated with an additional 20 weeks of SOC. Results from this cohort will be reported at a later date.

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 log10IU/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 1500 mg twice-daily with SOC for 4 weeks achieved undetectable HCV RNA levels with safety and tolerability comparable to placebo with SOC. Thirty percent (30%) of patients receiving R7128 500 mg twice-daily with SOC for 4 weeks achieved undetectable HCV RNA levels with safety and tolerability comparable to placebo with SOC. Ten percent (10%) of patients receiving placebo with SOC for 4 weeks achieved undetectable HCV RNA levels.

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV).

Pharmasset is currently developing three product candidates. Clevudine, for the treatment of chronic HBV infection, is enrolling Phase 3 clinical trials for registration in North, Central and South America and Europe. Clevudine is already approved for HBV in South Korea and marketed by Bukwang Pharmaceuticals in South Korea under the brand name Levovir. R7128, an oral treatment for chronic HCV infection, is in a Phase 1 clinical trial in combination with Pegasys(R) plus Copegus(R) through a strategic collaboration with Roche. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase 2 clinical trial.

For further information, see www.pharmasset.com.

8/08/08

Source

Pharmasset, Inc. Pharmasset Reports Preliminary Results of a 4-week Combination Study of R7128 for the Treatment of Chronic Hepatitis C. Press release. August 5, 2008.

DDW 2008: Antiviral Activity, Pharmacodynamics, and Quality of Life in Genotype 1 Hepatitis C Patients Treated with Albinterferon (Albuferon)

Albinterferon alfa-2b (albumin interferon; brand name Albuferon) is created by fusing interferon alfa with the human blood protein albumin, which enables it to last longer in the body. Albinterferon may be administered once every 2 to 4 weeks, compared with 3 times weekly for conventional interferon alfa and once-weekly for pegylated interferon alfa (Pegasys or PegIntron).