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HIV and Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria
Combination of 2 Nucleotide HCV Polymerase Inhibitors, PSI-7977 and PSI-938, Looks Good in Laboratory Study

SUMMARY: A combination of 2 complementary hepatitis C virus (HCV) polymerase inhibitors, PSI-7977 and PSI-938, demonstrated potent antiviral activity in a laboratory study, Pharmasset researchers reported at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. The company also recently announced promising results from a Phase 2a clinical trial of PSI-7977, and said that the first participants have started to receive therapy in a Phase 1 clinical trial of PSI-938.

By Liz Highleyman

Given the side effects and limited efficacy of interferon-based therapy for chronic hepatitis C, researchers are exploring a variety of direct-acting anti-HCV agents. To date, most of these drugs have been tested in combination with pegylated interferon plus ribavirin, but some studies are now evaluating all-oral regimens. To discourage emergence of resistance, investigators are looking at combinations of agents that target different steps of the viral lifecycle.

In a laboratory study, Veronique Zennou and colleagues from Pharmasset tested a combination of PSI-7977 plus PSI-938, and well as these candidates plus the HCV protease inhibitor telaprevir and a benzothiadiazine non-nucleoside polymerase inhibitor (NNRTI). They used replicon models of wild-type HCV and virus with various known resistance mutations.

While PSI-7977 and PSI-938 are both nucleotide analog prodrugs -- a pyrimidine and a purine analog, respectively -- they work by different mechanisms to interfere with the HCV NS5B polymerase enzyme, which is responsible for copying viral genetic material.


PSI-7977 plus PSI-938 demonstrated additive to synergistic (greater than the sum of the 2 drugs) activity.
This combination effectively cleared replicon models of both wild-type HCV and a strain with the NS5B polymerase S282T mutation.
PSI-7977 plus PSI-938 was more effective than telaprevir plus the NNRTI at clearing the wild-type replicon.
Either PSI-7977 or PSI-938 plus the NNRTI cleared wild-type and mutant replicons.
No emergence of new resistance mutations was detected.

Based on these findings the researchers concluded, "These in vitro results indicate that combinations of two nucleosides/tides targeting NS5b as well as direct-acting antivirals targeting different HCV proteins effectively suppress resistant replicons."

PSI-7977 in Phase 2a

Following the EASL meeting, on May 4, Pharmasset announced results from a Phase 2a study of PSI-7977 administered once-daily in combination with pegylated interferon alfa-2a (Pegasys) and ribavirin for 28 days in 63 previously untreated patients with genotype 1 chronic hepatitis C; standard therapy was then continued for an additional 44 weeks.

PSI-7977 demonstrated "potent short term antiviral activity and was generally safe and well tolerated," according to a press release issued by the company. All patients receiving PSI-7977 demonstrated continuous declines in HCV viral load with no viral breakthrough during 28 days of treatment; at all doses HCV RNA decreased by just over 5 log.

In an intent-to-treat analysis, 88% of patients in the PSI-7977 100 mg arm, 94% in the 200 mg arm, and 93% in the 400 mg arm achieved undetectable viral load (<15 IU/mL), significantly higher than the 21% response rate in the placebo plus standard therapy arm. Safety and tolerability were comparable to placebo across all PSI-7977 dose arms. No serious adverse events and no adverse events leading to treatment discontinuation were oberved. A full report of study findings will be presented at a scientific meeting later in 2010.

PSI-938 in Phase 1

In early April, Pharmasset announced the initiation of dosing in a Phase 1 single ascending dose study of PSI-938 in healthy HCV negative volunteers.

"PSI-938 is our first purine nucleotide analog to move into clinical development," said Pharmasset Chief Medical Officer Michelle Berrey in a company press release. "As PSI-938's resistance profile is different from other nucleoside/tides in development for HCV and it has a different metabolic pathway from pyrimidine analogs, such as RG7128 and PSI-7977, we believe PSI-938 could be potentially combined with other nucleosides in development to deliver a pan-genotype regimen. We look forward to reporting the first antiviral data with PSI-938 in the third quarter of 2010."

Pharmasset Inc., Princeton, NJ.



V Zennou, AM Lam, M Keilman, and others. Combination of two complementary nucleotide analogues PSI-7977 and PSI-938 effectively clears wild type and NS5b: S282T HCV replicons -- comparison with combinations of other antiviral compounds. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract 1034).

Other Sources

Pharmasset, Inc. Pharmasset Announces Results of a 28-day Phase 2a Study with PSI-7977 for the Treatment of Chronic Hepatitis C Infection. Press release. May 4, 2010.

Pharmasset, Inc. Pharmasset Initiates First Time in Human Study of PSI-938 for the Treatment of Hepatitis C: unique new HCV drug, nucleotide. Press release. April 13, 2010.