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AASLD 2011: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon

An all-oral dual regimen containing Pharmasset's hepatitis C virus (HCV) polymerase inhibitor PSI-7977 plus ribavirin produced 100% sustained response at 12 weeks in previously untreated people with HCV genotypes 2 or 3, according to findings from the ELECTRON study reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) this week in San Francisco.

With the approval this spring of the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek), direct-acting antiviral agents (DAAs) have begun to revolutionize hepatitis C treatment. Until recently, however, most clinical trials have combined investigational DAAs with pegylated interferon/ribavirin standard therapy, which has suboptimal effectiveness and causes side effects that lead many potential patients to delay or refuse therapy.

But several companies are now studying interferon-free oral regimens that combine DAAs that target different steps of the viral lifecycle; some also include ribavirin.

PSI-7977, a uridine nucleotide analog HCV polymerase inhibitor, has previously demonstrated promising safety and antiviral activity alone and in combination with standard therapy in people with HCV genotypes 1, 2, and 3.

Edward Gane from the New Zealand Liver Transplant Unit in Aukland and colleagues sought to determine whether and for how long pegylated interferon should be taken with PSI-7977 and ribavirin to produce the best outcomes.

A total of 40 participants with chronic hepatitis C received 400 mg PSI-7977 once-daily plus ribavirin for 12 weeks. In addition, they were randomly assigned to take pegylated interferon alfa-2a (Pegasys) for 4, 8, or 12 weeks, or not at all.

Because the researchers were uncertain whether the 2 oral drugs alone would work, they chose a population of relatively easy-to-treat patients who could be most easily "rescued" if the experimental regimen failed: treatment-naive people with HCV genotypes 2 (about one-third) or 3 (about two-thirds), and no cirrhosis; about 40% also had the favorable IL28B CC genotype. A majority were men, most were white, and the average age was about 48 years; concurrent use of methadone maintenance was allowed.

Results

• By week 4, all participants receiving PSI-7977 achieved HCV suppression below the limit of detection (15 IU/mL), regardless of pegylated interferon duration.
• All patients maintained undetectable HCV viral load at the end of PSI-7977 administration at week 12.
• All participants went on to achieve sustained virological response -- or continued undetectable HCV after the end of therapy -- at both 12 and 24 weeks post-treatment (SVR12 and SVR24, respectively).
• HCV viral kinetics did not differ between people receiving and not receiving pegylated interferon.
• No viral breakthrough was observed in any group, confirming that PSI-7977 has a high barrier to resistance.
• All participants receiving the PSI-7977 interferon-free regimen experienced ALT normalization.
• PSI-7977 plus ribavirin was general well-tolerated.
• Serious adverse events were most frequent in the 12-week pegylated interferon arm and least frequent in the interferon-free arm (72% vs 40%, respectively.
• No serious (grade 3 or 4) laboratory abnormalities, including blood cell deficiencies, were reported in the interferon-free arm.
• Use of ribavirin was still associated with anemia, but less so in the interferon-free arm.

"Potency, high barrier to resistance, and safety/tolerability allows interferon-free cures," the researchers concluded. "PSI-7977 has the potential to dramatically change the treatment paradigm for HCV in all genotypes and populations."

Gane noted that Pharmasset is now enrolling additional cohorts to look at interferon-free PSI-7977/ribavirin regimens in prior non-responders with genotypes 2 or 3, treatment-naive people with genotype 1, and prior null responders with genotype 1.

In light of these findings, the researchers asked what is the role of ribavirin. In an exploratory analysis, 10 patients received open-label PSI-7977 monotherapy. In this group HCV viral kinetics were "identical" with or without ribavirin, Gane said. No viral breakthrough was observed and 6 had sustained response up to 4 weeks after completing treatment. PSI-7977 monotherapy studies are also underway.

Pharmasset and Bristol-Myers Squibb announced this week that they are adding new trial arms looking at various 12-week, once-daily dual regimens combining PSI-7977 plus the investigational NS5A inhibitor daclatasvir (BMS-790052).

Investigator affiliations New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; Gastroenterology Department, Christchurch Hospital, Christchurch, New Zealand; Pharmasset, Inc, Princeton, NJ.

11/8/11

Reference

EJ Gane, CA Stedman, RH Hyland, et al. Once Daily PSI-7977 plus RBV: Pegylated interferon-Alfa not required for Complete Rapid viral response in Treatment-naive Patients with HCV GT2 or GT3. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 34.

Other Source

Pharmasset, Inc. and Bristol-Myers Squibb. New 12 Week, Interferon-Free Treatment Arms Added to All-Oral Combination Study of PSI-7977 and Daclatasvir (BMS-790052) for HCV Genotype 1. Press release. November 4, 2011.