Chemistry Reference
In-Depth Information
C
min
values following BID dosing, which appeared to correlate with the
observed antiviral activity. By including two cohorts with the same total daily
dose of 1500mg, but with one administered on a BID schedule, we were able to
determine that the BID regimen resulted in an additional 0.6 log
10
IUmL
1
decrease in HCV RNA.
27
Sequence analysis of patient samples was performed using both population
sequencing and clonal analysis. No mutations were identified that could be
associated with a resistant phenotype. In particular, no NS5B S282T variants-
which have been previously identified by in vitro replicon selection to have
reduced susceptibility to PSI-6130 and RG7128 (see above)-were detected.
12,23
11.3.2.3 28-Day Combination Study with RG7128 Added to
Pegasys
s
and Copegus
s
in HCV Genotype 1-Infected
Treatment-Naı¨ve Subjects
A 28-day study comparing SOC (Pegasys
s
and Copegus
s
) versus three dose
levels of RG7128 (500, 1000, and 1500mg, BID) added onto SOC was con-
ducted in treatment-naı¨ ve, HCV genotype 1 subjects. All doses were generally
well-tolerated. Adverse events at all doses of RG7128 were similar to those
reported for the SOC alone cohort. During the course of this investigation, the
500mg and 1500mg BID cohorts were studied initially and then a PK/phar-
macodynamic analysis was conducted to characterize the emerging dose-
response relationship. Using an E
max
model with change in HCV RNA from
baseline versus plasma trough drug concentrations, it appeared that the max-
imum antiviral effect had been achieved at the 1500mg BID dose and that a
modeled 1000mg BID dose would result in a similar level of antiviral activity.
Thus, a third cohort utilizing 1000mg BID was conducted to test this premise.
The effects on mean HCV RNA levels are shown in Table 11.4. As predicted,
the antiviral effects were essentially identical at the two higher doses and sub-
stantially less at the 500mg dose level. Maximum reductions were observed at
both the 1000mg and 1500mg dose levels, with mean HCV RNA dropping by
approximately 5 log
10
IUmL
1
. More importantly, after 28 days of RG7128
plus SOC, 30%, 88%, and 85% in the 500mg BID, 1000mg BID, and 1500mg
bid groups, respectively, had reached RVR (Rapid Virologic Response),
Table 11.4 Antiviral effects of R7128 after 28 days of therapy
500mg
BID
þ
SOC
1000mg
BID
þ
SOC
1500mg
BID
þ
SOC
SOC
a
Number of subjects
15
20
25
20
Mean log
10
change on
day 29
-2.85
-3.86
-5.05
-5.09
Percent subjects with
HCV RNA
o
15 IU
20
30
88
85
a
SOC
¼
Pegasys
s
þ
Copegus
s
.
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