Inhibitor PSI-7977 Works with Interferon or Companion Drug
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.
is working on a pair of complementary hepatitis C virus (HCV)
nucleotide polymerase inhibitors that were designed to work
(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.
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
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.
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).
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.
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.
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."
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
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
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
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
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
Pharmasset, Inc. Pharmasset Initiates Phase 2b ATOMIC Trial
of PSI-7977 for Multiple HCV Genotypes. Press release. March