Experimental HCV Polymerase Inhibitor R1626 Demonstrates Potent Viral Suppression,
but Often Causes Neutropenia By
Liz Highleyman Given
the limitations of current standard therapy
for chronic hepatitis C virus (HCV) using pegylated
interferon plus ribavirin, researchers are studying several novel directly-targeted
drugs that interfere with various steps of the HCV lifecycle. One
of these agents, Roche's
R1626, is a prodrug that is metabolized in the body to R1479, an HCV NS5B
polymerase inhibitor. Two recently published reports described early human clinical
trials of R1626.
Pharmacokinetics
and Resistance
As
reported in the March 18, 2008 advance online edition of Hepatology, Stuart
Roberts from the Alfred Hospital in Melbourne, Australia, and colleagues conducted
a randomized, placebo-controlled, multiple ascending dose, Phase 1b study to evaluate
the safety, pharmacokinetics, and antiviral activity of R1626, and to identify
the maximum tolerated dose in chronic hepatitis C patients.
In this study,
47 treatment-naive participants with chronic HCV
genotype 1 infection received oral R1626 at doses of 500 mg, 1500 mg, 3000
mg, or 4500 mg, or else placebo, twice daily for 14 days, with 14 days of follow-up.
Results
•
Doses up to and including 3000 mg twice daily were well tolerated after 14 days
of treatment.
•
There was an increased frequency of adverse events at the highest (4500 mg) dose.
•
Reversible mild-to-moderate hematological (blood) changes were observed with increasing
doses.
•
R1626 was efficiently converted to R1479 in the body, with dose-proportional pharmacokinetics
observed over the entire dose range.
•
The pharmacokinetics of R1479 were linear over the evaluated dose range.
•
Dose-dependent and time-dependent reductions in HCV RNA were observed.
•
Mean decreases in viral load after 14 days were 0.32 log10 with 500 mg, 1.2 log10
with 1500 mg, 2.6 log10 with 3000 mg, and 3.7 log10 with 4500 mg.
•
No resistance to R1479 was detected after 14 days of treatment with R1626.
In
conclusion, the authors wrote, these data support further studies of R1626 in
combination with peginterferon alfa-2a and ribavirin for the treatment of patients
with chronic HCV infection."
R1626
plus Pegylated Interferon Results
from just such a study were reported in the June 20, 2008 advance edition of the
same journal. Paul Pockros of the Scripps Clinic in La Jolla, CA, and colleagues
evaluated the efficacy and safety of R1626 administered for 4 weeks in combination
with pegylated
interferon alfa-2a (Pegasys) with or without ribavirin in previously untreated
patients with HCV genotype 1. Study
participants were randomly assigned to 1 of 4 arms:
•
1500 mg R1626 twice daily + pegylated interferon (n = 21);
•
3000 mg R1626 twice daily + pegylated interferon (n = 32);
•
1500 mg R1626 twice daily + pegylated interferon + ribavirin (n = 31);
•
Pegylated interferon + ribavirin with no R1626 (standard of care) (n = 20).
•
At 4 weeks, HCV RNA was undetectable (< 15 IU/mL) in 29% of patients in the
dual 1500 mg arm, 69% in the dual 300 mg arm, and 74% in the triple 1500 mg arm,
compared with only 5% in the standard of care arm.
•
Mean reductions in HCV RNA from baseline to week 4 were 3.6, 4.5, 5.2, and 2.4
log10 IU/mL, respectively.
•
Synergy was observed between R1626 and pegylated interferon, and between R1626
and ribavirin.
•
There was no evidence of development of viral resistance mutations.
•
Adverse events were mainly mild or moderate.
•
7 patients experienced 9 serious adverse events (including 1 patient with a serious
event in the standard of care arm).
•
The incidence of grade 4 neutropenia (low white blood cell count) was 48%, 78%,
39%, and 10%, respectively, in the 4 arms, and this was the main reason for dose
reduction.
In
conclusion, the study authors wrote, "A synergistic antiviral effect was
observed when R1626 was combined with peginterferon
alfa-2a [with or without] ribavirin."
"Dosing of R1626 was
limited by neutropenia," they continued, adding that a study of different
dosages of R1626 in combination with pegylated interferon and ribavirin is underway. 
7/15/08
References
SK
Roberts, G Cooksley, GJ Dore, and others. Robust antiviral activity of R1626,
a novel nucleoside analog: A randomized, placebo-controlled study in patients
with chronic hepatitis C. Hepatology March 18, 2008 [Epub ahead of print].
PJ Pockros,
D Nelson, E Godofsky, and others. R1626 plus peginterferon Alfa-2a provides potent
suppression of hepatitis C virus RNA and significant antiviral synergy in combination
with ribavirin. Hepatology. June 20, 2008 [Epub ahead of print]. |
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