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.
Results
 |
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.
5/11/10
Reference
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.
