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AASLD 2011: High Sustained Response Rates with PSI-7977 Plus Pegylated Interferon/Ribavirin

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Adding the hepatitis C virus (HCV) polymerase inhibitor PSI-7977 to pegylated interferon plus ribavirin produced a 91% cure rate for previously untreated patients with hard-to-treat HCV genotype 1, according to results from the PROTON study presented this month at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) in San Francisco.

The advent of direct-acting antiviral agents (DAAs) that target different steps of the HCV lifecycle has ushered in a new paradigm in hepatitis C treatment. Trials of all-oral regimens are underway, but studies that are further along have mostly tested DAAs with pegylated interferon/ribavirin in an effort to increase response rates and shorten treatment duration.

The Phase 2b PROTON study evaluated the safety and efficacy of PSI-7977, Pharmasset's once-daily uridine nucleotide analog HCV polymerase inhibitor, added to pegylated interferon alfa-2a (Pegasys) and ribavirin.

At AASLD Eric Lawitz from Alamo Medical Research presented 12-week sustained virological response (SVR12) outcomes -- or continued undetectable HCV RNA 12 weeks after completion of treatment -- for patients with HCV genotype 1.

Data presented earlier this year showed that 96% of patients with easier-to-treat genotypes 2 or 3 achieved SVR12 using PSI-7977 plus pegylated interferon/ribavirin for 12 weeks.

The genotype 1 analysis included 121 treatment-naive patients. Approximately half were men, the median age was about 50 years, about 75% were white, 20% were black, and 10% were Hispanic. About 75% had HCV subtype 1a and about 40% had the favorable IL28B CC gene pattern; people with liver cirrhosis were excluded.

Participants were randomly assigned to receive 200 mg or 400 mg once-daily PSI-7977 plus pegylated interferon/ribavirin for 12 weeks, continuing on pegylated interferon/ribavirin alone for another 12 weeks. At that point, those with extended rapid virological response (eRVR) stopped treatment, while non-eRVR patients continued on a pegylated interferon/ribavirin "tail" through week 48. A control arm received pegylated interferon/ribavirin standard therapy for 48 weeks.

Results

  • All participants receiving either dose of PSI-7977 experienced rapid HCV viral load suppression.
  • Rapid virological response (RVR), undetectable HCV RNA at week 4:
    • 98% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
    • 98% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
    • 19% of patients receiving pegylated interferon/ribavirin alone.
  • End-of-treatment response at week 12:
    • 91% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
    • 91% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
    • 50% of patients receiving pegylated interferon/ribavirin alone.
  • SVR12:
    • 88% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
    • 91% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
    • Patients receiving pegylated interferon/ribavirin standard therapy are still undergoing follow-up for SVR.
  • The SVR12 rate reached 98% among patients who received at least 8 weeks of 400 mg PSI-7977.
  • All but 1 patient in the 2 PSI-7977 arms qualified for 24 total weeks of treatment according to response-guided therapy.
  • No PSI-7977 recipients experienced viral breakthrough while on PSI-7977, but 3 people in the 200 mg group did so while on the pegylated interferon/ribavirin tail.
  • 1 person each in the 200 mg and 400 mg groups experienced post-treatment relapse, none of whom showed evidence of the S282T resistance mutation.
  • PSI-7977 was generally well-tolerated with an adverse events profile similar to that of pegylated interferon/ribavirin standard therapy.
  • Insomnia was more common in the 400 mg PSI-7977 arm (15% vs 8% in control arm and 4% in 200 mg PSI-7977 arm).
  • There were no treatment discontinuations due to adverse events related to PSI-7977

The researchers noted that the high SVR rate among HCV genotype 1 patients was independent of predictors of poor interferon response.

Lawitz elaborated that among the 13 PROTON participants with the unfavorable IL28B TT pattern, all had a "brisk response" and all achieved SVR12.

Another study presented at AASLD, called ELECTRON, showed that PSI-7977 plus ribavirin -- but without pegylated interferon -- produced a 100% SVR12 rate for genotype 2 and 3 patients. This regimen will be carried forward in further studies of patients with all genotypes.

Investigator affiliations: Alamo Medical Research, San Antonio, TX; Quest Clinical Research, San Francisco, CA; Southern California Liver Ctr, Coronado, CA; VMMC, Seattle, WA; Cedars Sinai Med Ctr, Los Angeles, CA; GI Specialists of Georgia, Marietta, GA; Beth Israel Deaconess, Boston, MA; North Shore University Hospital, Manhassett, NY; OIC, Orlando, FL; Kansas City Gantroenterology and Hepatology, LLCG, Kansas City, MO; University of Florida, Gainesville, FL; Mount Sinai, New York, NY; Cornell University, New York, NY; University of Chicago, Chicago, IL; Alabama Liver and Digestive Specialists, Montgomery, AL; University of North Carolina, Chapel Hill, NC; Fundacion de Investigacion De Diego, San Juan, Puerto Rico; University of Pennsylvania, Philadelphia, PA; Johns Hopkins University, Lutherville, MD; California Pacific Medical Center, San Francisco, CA; ACRI, Anaheim, CA; Columbia Gastroenterology, Columbia, SC; Pharmasset, Inc., Princeton, NJ.

11/22/11

Reference

E Lawitz, JP Lalezari, T Hassanein, et al. Once-Daily PSI-7977 Plus Peg/RBV in Treatment-naïve Patients with HCV GT1: Robust End of Treatment Response Rates are Sustained Post-treatment. 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 225.