R7128
Demonstrates Potent Anti-HCV Activity in Combination with Pegylated Interferon/Ribavirin;
Ongoing Trial to be Expanded
By
Liz Highleyman Since
many patients with chronic hepatitis C virus (HCV)
infection do not achieve sustained virological response (SVR) with standard
therapy consisting of pegylated interferon
plus ribavirin, researchers have explored directly targeted antiviral agents
that attack various stages of the HCV lifecycle. One
such agent is R7128,
an oral pro-drug of the nucleoside analog HCV polymerase inhibitor PSI-6130 being
developed jointly by Pharmasset and Roche. Interim results from a Phase 1 study
of R7128 were presented at the 43rd annual meeting of the
European Association for the Study of the Liver (EASL) last week in Milan. This
randomized multicenter trial evaluated 2 doses of R7128 plus 180 mcg/week pegylated
interferon alpha-2a (Pegasys) plus 1000-1200 mg/day ribavirin (Copegus) for
28 days in treatment-naive genotype 1 chronic hepatitis C patients. Cohort 1 (n
= 25) received 500 mg twice-daily (BID) R7128 or placebo plus standard therapy,
while Cohort 2 received 1500 mg BID R7128 (n = 25). Results
•
85% of patients
receiving the 1500 mg BID dose of R7128 achieved undetectable HCV RNA after 4
weeks, compared with 30% in the 500 mg R7128 arm and 10% in the placebo control
arm.
•
Mean HCV RNA
decreases at week 4 were 5.12 log10 IU/mL in the 1500 mg R7128 arm, 3.82 log10
in the 500 mg arm, and 2.95 log10 in the control arm.
•
Responses were
similar in patients with HCV genotypes 1a and 1b.
•
Safety and
tolerability were similar to those seen with pegylated interferon/ribavirin standard
therapy.
•
Most adverse
events were mild to moderate; no serious adverse events were reported.
•
The most common
adverse events (reported by at least 15% of patients in any group) were headache,
injection site reactions, muscle and joint aches, fatigue, chills, rash, nausea,
diarrhea, fever, dizziness, stomach upset, and itching.
•
10%-15% of
patients in the R7128 arms experienced Grade 3/4 neutropenia, compared with 30%
of placebo patients.
•
15% of patients
receiving R7128 and 10% receiving placebo experienced Grade 3 changes in hemoglobin
(an indicator of anemia).
•
There were
no clinically significant changes in other laboratory safety parameters, vital
signs, or electrocardiograms (ECGs).
•
Overall, there
was no clinical evidence of any major organ toxicities related to R7128.
Conclusion Based
on these findings, the researchers concluded that R7128
"demonstrated clinically significant antiviral potency" in combination
with pegylated
interferon/ribavirin, with a safety profile similar to that of standard therapy. "R7128,
in combination with Pegasys plus Copegus, has demonstrated rapid virologic response
(RVR) percentages in a 4-week study that are similar to HCV protease inhibitors
and has an encouraging short-term clinical safety profile," said Dr. John
McHutchison of Duke University Medical Center in a press release issued by Pharmasset.
The company
recently announced that it would expand its Phase 1 development program to test
R7128 in patients with HCV genotypes 2 and 3 (see press release below). Duke
Clinical Research Institute, Durham, NC; Quest Clinical Research, San Francisco,
CA; Auckland Clinical Studies Limited, Auckland, New Zealand; Fundacion de Investigacion
de Diego, Santurce, PR; Orlando Immunology Center, Orlando, FL; University of
Florida, Gainesville, FL; University of Colorado, Aurora, CO; Weill Medical College
of Cornell University, New York, NY; University of Pennsylvania, Philadelphia,
PA; Roche, Palo Alto, CA; Pharmasset, Princeton, NJ.
Below is an edited
excerpt of a press release from Pharmasset describing expansion of clinical trials
of R7128: Pharmasset
Adds Two Cohorts to R7128 Hepatitis C Study Two
4-week cohorts will be enrolled to evaluate R7128 1500 mg BID in HCV genotypes
2 and 3 prior non-responders and R7128 1000 mg BID in HCV genotype 1 treatment-naive
patients
PRINCETON, N.J. and MILAN, Italy, April 24, 2008 -- Pharmasset,
Inc. (Nasdaq: VRUS) will enroll two additional cohorts in the ongoing Phase 1
study protocol to evaluate 4 weeks of combination therapy with R7128. R7128, a
prodrug of PSI-6130, is a nucleoside analogue polymerase inhibitor of hepatitis
C virus (HCV) that is being developed through Pharmasset's collaboration with
Roche.
Cohort 3 will study R7128 1000 mg BID in treatment-naive patients
with HCV genotype 1. This cohort is intended to provide clinical antiviral activity
data in support of pharmacokinetic models from earlier studies. Cohort 4 will
study R7128 1500 mg BID in patients with HCV genotypes 2 and 3 who did not achieve
a sustained virologic response (SVR) with previous interferon-based therapy. Cohorts
3 and 4 will both be dosed in combination with Pegasys (peginterferon alfa-2a)
plus Copegus (ribavirin).
Patients in Cohorts 3 and 4 are scheduled to
begin dosing by the end of May 2008. Preliminary safety and antiviral activity
data from the 4-week combination studies are anticipated during the 3rd quarter
of 2008. Cohorts 3 and 4 will be conducted in parallel with the global Phase 2b
study preparation activities for R7128. The timing of the Phase 2b study is not
dependent upon data from Cohorts 3 and 4.
"Our pharmacokinetic modeling
of the 500 mg and 1500 mg cohorts of R7128 in combination with Pegasys plus Copegus
suggests that the 1000 mg dose could deliver a rapid virologic response (RVR)
rate similar to the 1500 mg dose," stated Dr. Michelle Berrey, Pharmasset's
Chief Medical Officer. "The confirmatory results from this additional cohort
will aid us in selecting the appropriate doses to evaluate in the global Phase
2b study that is being planned to evaluate R7128 in triple combination for up
to 12 weeks."
"R7128 is equally potent in vitro against HCV
genotypes 1, 2, 3, and 4, and we believe it is clinically and commercially important
to test R7128 in patients with these HCV genotypes," stated Schaefer Price,
Pharmasset's Chief Executive Officer. "Twenty percent of U.S. HCV-infected
patients and approximately 30% of European and Latin American HCV-infected patients
have genotypes 2 and 3. These patients are currently treated with 24 weeks of
pegylated-interferon plus ribavirin, but 20% of this population fails to achieve
an SVR. By potentially addressing this unmet medical need in a patient population
for whom the standard of care is only 24 weeks, we could possibly design shorter
clinical trials that may provide a quicker path to the market for R7128."
About R7128
R7128 is being developed for the treatment
of chronic HCV infection. R7128 is a prodrug of PSI-6130, a cytidine nucleoside
analog inhibitor of HCV RNA polymerase. A prodrug is a chemically modified form
of a molecule designed to enhance the absorption, distribution and metabolic properties
of that molecule. Results from an oral single ascending dose study of PSI-6130
in 24 healthy male volunteers showed that PSI-6130 was generally well tolerated
with no serious adverse events in doses up to 3000 mg.
R7128 demonstrated
potent, dose-dependent antiviral activity across four prior treatment-failure
patient cohorts (n = 40) receiving 750 mg or 1500 mg administered either once-daily
or twice-daily for 14 days as monotherapy. The greatest mean decrease in HCV RNA
from baseline was demonstrated in the patient cohort that received 1500 mg twice-daily,
the highest dose of R7128 administered in the study. These patients demonstrated
a mean 2.7 log10 IU/mL (>99%) decrease in HCV RNA. There was no evidence of
the development of viral resistance in any dose cohort after 14 days of dosing.
In a 4-week Phase 1 combination study that was conducted in 50 treatment-
naive patients chronically infected with HCV genotype 1, R7128 demonstrated potent
short-term antiviral activity and was generally safe and well tolerated. Eighty-five
percent (85%) of patients receiving R7128 1500 mg twice-daily (BID) with Pegasys
plus Copegus for 4 weeks achieved undetectable HCV RNA levels with safety and
tolerability comparable to placebo with Pegasys plus Copegus.
About
Pharmasset
Pharmasset is a clinical-stage pharmaceutical company
committed to discovering, developing and commercializing novel drugs to treat
viral infections. Pharmasset's primary focus is on the development of oral therapeutics
for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human
immunodeficiency virus (HIV).
For further information, see www.pharmasset.com. |
4/29/08 Reference
J
Lalezari, E Gane, M Rodriguez-Torres, and others. Inhibitor R7128 with Peg-IFN
and Ribavirin: Interim Results of R7128 500mg BID for 28 Days. 43rd annual meeting
of the European Association for the Study of the Liver (EASL 2008). Milan, Italy.
April 23-27, 2008.
Additional Source
Pharmasset , Inc. Pharmasset
Adds Two Cohorts to R7128 Hepatitis C Study. Press release. April 24, 2008. |
