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HIV and Coverage of the
46th Annual Meeting of the European
Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Polymerase Inhibitor PSI-7977 Works with Interferon or Companion Drug

SUMMARY: Almost all treatment-naive hepatitis C patients treated with Pharmasset's candidate PSI-7977 plus pegylated interferon/ribavirin experienced 12-week sustained response, and more than 90% treated with a PSI-7977 + PSI-938 all-oral combo had undetectable HCV at 14 days, researchers reported at EASL.

By Liz Highleyman

Pharmasset is working on a pair of complementary hepatitis C virus (HCV) nucleotide polymerase inhibitors that were designed to work together, PSI-7977 (a pyrimidine analog) and PSI-938 (a purine analog). In preclinical studies the drugs showed promising antiviral activity when combined with pegylated interferon/ribavirin, a non-nucleoside polymerase inhibitor, or each other.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) last week in Berlin, 3 research teams presented data on PSI-7977. Two analyses from the Phase 2b PROTON study looked at PSI-7977 used in combination with standard therapy (pegylated interferon/ribavirin) in people with HCV genotype 1 and in those with genotypes 2 or 3. The third presentation showed early results from a study of PSI-7977 + PSI-938 in various combinations taken for 2 weeks.

PSI-7977 Genotype 1

The first PROTON analysis included 121 treatment-naive chronic hepatitis C patients with hard-to-treat HCV genotype 1. About 80% were white and the median age was around 50 years, but the proportion of men varied from 45% to 73% in different study arms. About 40% had the favorable CC IL28B gene pattern, which is associated with better response to interferon.

Participants were randomly assigned to receive PSI-7977 at doses of either 200 mg or 400 mg once-daily, or else placebo, in combination with standard doses of pegylated interferon and ribavirin for 12 weeks. At that point, people who started on triple therapy and experienced rapid virological response (RVR), or undetectable HCV RNA at week 4, took pegylated interferon/ribavirin for an additional 12 weeks; those without RVR continued on pegylated interferon/ribavirin for 36 weeks (thereby reaching the standard duration of 48 weeks).

All but 1 participant in both PSI-7977 dose arms had undetectable HCV viral load (< 15 IU/mL) at week 4. At week 12, 100% in the 200 mg arm and 92% in the 400 mg arm were undetectable (compared with about 60% in the standard therapy arm). No viral breakthrough occurred in any patient who stayed on treatment through week 12. Taken together, 95% of participants who received either dose of PSI-7977 had undetectable HCV from week 4 to 12. Viral load declines did not differ according to IL28B status.

Overall, there were no significant differences in adverse events between participants who received the PSI-7977 combination and those on standard therapy. A total of 4 patients discontinued treatment prior to 12 weeks, 3 of them due to adverse events considered unrelated to PSI-7977. None discontinued due to drug-related adverse events and there were no dose-related blood, liver, or kidney toxicities.

These findings led the researchers to conclude, "High on-treatment response, lack of viral breakthrough, and a promising safety profile support continued exploration of PSI-7977 with abbreviated interferon duration and/or other [direct-acting antivirals] in patients with all HCV genotypes."

PSI-7977 Genotype 2 or 3

The second PROTON analysis looked at 25 treatment-naive patients with HCV genotypes 2 or 3. About two-thirds were men, the median age was 47, and 28% had the favorable CC IL28B pattern.

This portion of the study was open-label and all participants received 400 mg PSI-7977 in combination with pegylated interferon/ribavirin for 12 weeks. It also had longer follow-up at the time of presentation, enabling researchers to report sustained virological response rates 12 weeks after completion of therapy, or SVR-12.

One participant was lost to follow-up after the first day. All of the 24 remaining patients experienced RVR and complete early virological response (cEVR), which in this case was also an end-of-treatment response. In an intent-to-treat analysis, 96% of patients achieved SVR-12 -- or 100% if counting only those who stayed in the study. Since everyone responded, it was not possible to analyze what baseline factors contributed to good response.

Again, PSI-7977 was generally well-tolerated. Side effects were uncommon overall, and there were no serious adverse events or discontinuations due to drug-related adverse events.

This research team conclude that the drug's "[f]avorable risk:benefit [ratio] supports studies in patients with advance disease and broad HCV genotype distribution."

PSI-7977 + PSI-938

Finally, the NUCLEAR study tested a combination of PSI-7977 + PSI-938 over 14 days, looking at safety, pharmacokinetics, antiviral activity, and interactions between the 2 drugs.

A total of 40 treatment-naive chronic hepatitis C patients with HCV genotype 1 were allocated into 4 cohorts (each with 8 receiving active drug and 2 receiving placebo). Most were men and the median age was about 45 years.

Cohort 1 received 300 mg once-daily PSI-938 for the full 14 days. Cohort 2 received 300 mg once-daily PSI-938 for 7 days, followed by the combination during the second week. Cohort 3 did the opposite, taking 400 mg once-daily PSI-7977 during the first week and the combination during the second week. Cohort 4 took the same doses of both drugs for the entire 2-week period.

HCV viral load declined rapidly in all treatment arms. Some individuals reached undetectable viral load in as few as 3 days. In all arms, HCV RNA fell by about 4.5 logs by the end of week 1 and by about 5.0 logs by the end of week 2. By the end of the study period 50% of participants in cohort 1, 100% in cohort 2, and 88% in both cohort 3 and 4 achieved undetectable HCV RNA. Taken together, 92% of patienst who received any combination of the PSI-938 + PSI-7977 fell below the limit of detection.

Both drugs, and the combination, were generally safe and well-tolerated. Five adverse events, all mild, were considered possibly related to study drugs. There were no serious adverse events, clinically significant laboratory abnormalities, or drug discontinuations for any reason.

"PSI-938 + PSI-7977 is the first purine + pyrimidine combination explored in HCV," the investigators stated. "Monotherapy with either nucleotide analog provided profound antiviral responses rivaling the best antiviral responses reported by combinations employing 2 or more [direct-acting antivirals]."

"Data support progression to a Phase 2 combination study including PSI-938 and PSI-7977," they concluded.

On March 30 Pharmasset announced that it has started enrollment for the ATOMIC study, a Phase 2b trial in which previously untreated patients with HCV genotypes 1, 4, 5, or 6 will receive 400 mg once-daily PSI-7977 in combination with pegylated interferon/ribavirin for 12 or 24 weeks.

In addition, the NUCLEAR investigators noted that another Phase 2 study enrolling people with all HCV genotypes will explore different durations of the PSI-7977 + PSI-938 pyrimidine/purine combination.



DR Nelson, J Lalezari, E Lawitz, et al. Once daily PSI-7977 plus Peg-IFN/RBV in HCV GT1: 98% rapid virologic response, complete early virologic response: the PROTON study. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 9.

J Lalezari, E Lawitz, M Rodriguez-Torres, et al. Once daily PSI-7977 plus PegIFN/RBV in a Phase 2b trial: rapid virologic suppression in treatment-naive patients with HCV GT2/GT3. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 325.

E Lawitz, M Rodriguez-Torres, J Denning, et al. Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA < load at day 14: first purine/pyrimidine clinical combination data (the NUCLEAR study). 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 8.

Other Source
Pharmasset, Inc. Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes. Press release. March 30, 2011.
























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