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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.

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.

DDW 2008: Significance of Transient HCV Viral Load

Response to treatment for chronic hepatitis C virus (HCV) infection is measured in terms of reduction in HCV RNA level, or viral load. End-of-treatment response (ETR) is defined as undetectable HCV RNA at the completion of therapy (24 or 48 weeks, depending on HCV genotype). Sustained virological response (SVR) - typically considered a "cure" - is continued undetectable viral load 24 weeks after completion of treatment.

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.

EASL 2008: Boceprevir Added to Pegylated Interferon/Ribavirin Increases Sustained Response in Treatment-naive Patients and Some Prior Non-responders

About half of all people with chronic hepatitis C virus (HCV) infection achieve a cure, or sustained virological response (SVR), with the standard treatment of pegylated interferon plus ribavirin; rates are even lower for patients with difficult-to-treat HCV genotype 1. Thus, researchers have studies various antiviral agents that directly target various stages of the HCV lifecycle.

At the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, researchers presented data on Schering-Plough's investigational oral HCV NS3 serine protease inhibitor boceprevir (formerly known as SCH503034).

Triple Combination Therapy

In a late-breaker session, Paul Kwo of Indiana University School of Medicine and colleagues presented interim results from HCV SPRINT-1, a Phase 2 study assessing the safety and efficacy of boceprevir in combination with pegylated interferon and ribavirin in 595 treatment-naive patients with genotype 1 chronic hepatitis C treated in the U.S. (77%), Canada, and Europe; 16% were black (a group that responds less well to interferon-based therapy) and 7% had liver cirrhosis at baseline.

Participants were randomly allocated to various regimens containing 800 mg twice-daily boceprevir, 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron), and weight-based ribavirin (Rebetol):

• Boceprevir plus pegylated interferon plus 800-1400 mg/day ribavirin for 28 or 48 weeks (no lead-in arm);

• Pegylated interferon plus ribavirin for 48 weeks (standard therapy control arm).

The rationale for this novel approach, according to Schering-Plough, is that both pegylated interferon and ribavirin reach steady-state concentrations by week 4; therefore, patients in the lead-in arm would have boceprevir added after the other drugs have already reached optimal levels. Further, pegylated interferon will have activated the immune system by the time boceprevir is added. Researchers hope this strategy might minimize "functional monotherapy" with the protease inhibitor before high enough levels of pegylated interferon and ribavirin are achieved, which may reduce the risk of drug resistance.

The primary study endpoint of the study will be SVR, or undetectable HCV RNA (below 15 IU/mL) 24 weeks after completion of treatment. For the interim analysis, researchers presented response rates 12 weeks after completion of therapy -- or "SVR12" -- in the 28-week arms. This data was not yet available for participants treated for 48 weeks.

Results

• In an intent-to-treat analysis, the SVR rate in the lead-in, 28-week, full-dose ribavirin arm was 57%, compared with 55% in the arm that received triple therapy from the outset.

• Similar results were seen at week 12 (79%, 69%, and 34%, respectively).

• RVR, or undetectable HCV RNA after 4 weeks of boceprevir, was a good predictor of sustained response.

• 11%-15% of patients discontinued treatment in the boceprevir arms, compared with 8% in the control arm.

• The incidence of rash-related adverse events was similar in the boceprevir-containing arms and the pegylated interferon/ribavirin control arm.

Based on these findings, the investigators concluded, "Four weeks of treatment with [pegylated interferon/ribavirin] prior to boceprevir administration markedly increased RVR and EVR and reduced viral breakthrough by 50%."

"This new treatment paradigm has the potential to maximize efficacy of multi-drug combinations and minimize the risk of resistance by identifying responders to [pegylated interferon/ribavirin]," they continued. "Interim results also demonstrate that full dose ribavirin is optimal."

"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 Dr. Kwo in a press release issued by Shering-Plough. "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."

Final results from SPRINT-1 are expected to be available in early 2009.

Indiana University School Of Medicine, Indianapolis, IN; Alamo Medical Research, San Antonio, TX; Mount Vernon Endoscopy Center, Alexandria, VA; University of Miami Center for Liver Diseases, Miami, FL; Baylor College of Medicine, Houston, TX; Indianapolis Gastroenterology Research Foundation, Indianapolis, IN; South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Henry Ford Hospital, Detroit, MI; Digestive Disease Associates, Baltimore, MD; Univ Of California-Davis, Sacramento, CA; Liver and Intestinal Research Center, Vancouver, Canada; Weill Medical College Of Cornell Univ, New York NY; Digestive Healthcare Of Georgia, Atlanta, GA; Schering-Plough Research.

Null Responders

In a related study, researchers looked at response to boceprevir combination therapy in 357 "null responders" with genotype 1 HCV who had less than a 2 log10 drop in HCV RNA after 12 weeks of prior treatment with pegylated interferon/ribavirin, or failure to achieve undetectable viral load if treated longer than 12 weeks.

Participants received 1.5 mcg/kg/week pegylated interferon (PegIntron) plus boceprevir at doses of 100, 200, 400, or 800 mg, some with ribavirin. The control arm received standard therapy, adding boceprevir if HCV remained detectable. Early data showed that the lower doses of boceprevir were less effective, so all patients who demonstrated virological response to boceprevir switched to triple combination therapy using 800 mg boceprevir for an additional 24 weeks.

SVR rates ranged from 2% in the control group to 14% using the boceprevir regimens studied, though no patients received triple therapy with the highest dose of boceprevir for the full treatment period. Individuals who experienced a viral load decrease greater than 2 log10 at week 12 were most likely to achieve undetectable HCV RNA on triple therapy. Boceprevir resistance mutations were detected in a majority of subjects who did not achieve SVR.

The investigators concluded that, "Some 'null' responders to [pegylated interferon/ribavirin] can achieve an SVR with [pegylated interferon/ribavirin/800 mg boceprevir], but response is dependent on residual interferon responsiveness." They added that, "Treatment failures to [pegylated interferon/ribavirin] with > 2 log10 viral drop at [week 12] may be good candidates" for triple therapy.

University of Miami School of Medicine, Miami, FL; Cedars-Sinai Medical Center, Los Angeles, CA; Weill Medical College of Cornell University, New York, NY; Northwestern University, Chicago, IL; St. Louis University, St. Louis, MO; Alamo Medical Research, San Antonio, TX; Henry Ford Hospital, Detroit, MI; Duke University Medical Center, Durham, NC; Liver Institute at Methodist Dallas, Dallas, TX; A.P.H. Paris, Hopital Pitie-Salpetriere, Paris, France; Johns Hopkins Univ, Baltimore MD; Hospices Civils De Lyon Hotel Dieu, Lyon, France; Opedale Molinette, Torino, Italy; Univsitaetsklinikum Des Saarlandes, Homburg/Saar, Germany.

Boceprevir Resistance Mutations

Finally, researchers presented results from a clonal analysis of mutations in the HCV NS3 protease domain in non-responders treated with boceprevir.

HCV RNA was assessed at baseline, day 14 (end-of-treatment), and day 28 (end-of-follow-up) in samples collected from 22 patients treated with 400 mg boceprevir 2 or 3 times daily.

Mutations were detected at 51 different amino acid positions within the NS3 protease, with a frequency greater than 5% by the end of treatment. Mutations at 5 amino acid positions (V36, T54, R155, A156, V170) previously shown to confer resistance to boceprevir in vitro were detected in 14 patients. However, no mutations at position A156 were detected at the end-of-follow-up.

J W Goethe University Hospital, Medizinische Klinik I, 60590 Frankfurt am Main, Germany; Saarland University Hospital, Klinik für Innere Medizin II, Homburg, Germany; Schering Plough, Kenilworth, NJ.

4/29/08

References

P Kwo, E Lawitz, J McCone, and others. Interim Results from HCV SPRINT-1: RVR/EVR from Phase 2 Study of Boceprevir Plus PegINTRON (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naïve Subjects with Genotype-1 CHC. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

E Schiff, F Poordad, I Jacobson, and others. Boceprevir (B) Combination Therapy in Null Responders (NR): Response Dependent on Interferon Responsiveness. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

S Susser, MW Welker, M Zettler, and others. Clonal Analysis of Mutations Selected in the HCV NS3 Protease Domain of Genotype 1 Non-Responders Treated with Boceprevir (SCH503034). 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Source

Schering-Plough Corporation. Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL. Press release. April 26, 2008.

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.

Acute HIV-HCV Coinfection Increasingly Common in U.K.; HCV Superinfection Reported in France

Several outbreaks of apparently sexually transmitted acute hepatitis C virus (HCV) infection have been reported in recent years in large cities in the U.K. and Europe, primarily among HIV positive men who have sex with men (MSM)Two new reports on sexually transmitted HCV in HIV positive men were published in the March 12, 2008 issue of AIDS.

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).

Methamphetamine Promotes Hepatitis C Virus Replication in Human Liver Cells

While there have been numerous studies of hepatitis C in individuals who inject drugs (primarily heroin), less is known about the effects of non-injection drugs on hepatitis C virus (HCV) infection. Methamphetamine is a stimulant that may be taken as a pill, injected, snorted, smoked, or administered anally. In the April 2008 Journal of Viral Hepatitis, L. Ye of the University of Pennsylvania School of Medicine and colleagues reported on a laboratory study looking at whether methamphetamine inhibits innate immunity in host cells, thereby facilitating HCV replication in human hepatocytes (liver cells).