Monday Poster Sessions, October 30, 2006
Presidential Plenary Session
T. Kieffer; C. Sarrazin; J. Miller; S. Traver;
Y. Zhou; D. Bartels; B. Hanzelka; U. Müh; C. Lin; H. Reesink; A. Kwong; S. Zeuzem.
Background:
Telaprevir (VX-950) is an orally-active HCV
protease inhibitor that profoundly reduced plasma HCV RNA in genotype 1 patients
during 14 days of dosing alone (median 4.4-log10 decline in optimal dose group)
and in combination with peg-IFN-alfa (peg-IFN) (median 5.5-log10 decline).
Using a highly sensitive sequencing assay that detects minor populations of
viral variants (≥5%), mutations were identified in a previous clinical
study that conferred low-level (V36M/A, T54A, or R155K/T) or high-level
resistance (A156V/T and 36/155) in vitro. These variants were sensitive to IFN
in the HCV replicon system. We now report a detailed kinetic analysis of these
variants in a second study of 14 days of dosing with telaprevir
(750 mg q8h) alone (n=8) or in combination with peg-IFN (n=8).
Methods:
Plasma HCV RNA was isolated at days 4, 8, 12, and 14 during
dosing and 7-10 days after dosing. The NS3 protease domain cDNA
was amplified by nested RT-PCR, cloned and sequenced with a lower limit of
detection (LLD) of 100 IU/mL. Sequence changes were analyzed from about 75
clones/patient/time point.
Results:
In patients dosed with telaprevir/peg-IFN,
wild-type virus was detected at day 4, and either wild-type or resistant virus
was observed at day 8 in 4 of 8 patients with HCV RNA levels above the LLD.
Viral levels continued to decline in all patients. All 8 patients began
standard therapy (peg-IFN/RBV) and their HCV RNA levels were undetectable 3
months after the 14-day study period.
Among patients dosed with telaprevir
alone, four patients had a breakthrough or plateau response. In these patients,
R155 and A156V/T variants were detectable by day 8, and the V36(M/A)/R155(K/T)
variant predominated by day 14. Four other patients dosed with telaprevir alone all had a continuous decline in HCV RNA
levels. Two of these patients had A156V/T uncovered by day 8, while the other
two had levels below LLD.
Conclusions:
The rapid and dramatic antiviral response to telaprevir reflects a sharp reduction in wild-type virus.
Viral variants were uncovered as wild-type virus was cleared. HCV RNA levels
can decline in patients receiving telaprevir
monotherapy, even in those with detectable A156V/T variant. Viral rebound with
monotherapy appears to result from the presence of V36(M/A)/R155(K/T); this
could be due to greater fitness of this variant compared to A156V/T. The
combination of telaprevir and peg-IFN suppressed
resistant variants, indicating that these variants are fully sensitive to
peg-IFN.
E.
Lawitz; T. Nguyen; Z. Younes;
J. Santoro; N. Gitlin; D. McEniry;
R. Chasen; J. Goff; S. Knox; K. Kleber;
B. Belanger; N. A. Brown; D. Dieterich; I. The 006.
Background:
Valopicitabine (NM283) showed dose-related anti-HCV activity,
alone and combined with pegylated interferon (NM283/pegIFN) in trials of
patients with hepatitis C (HCV genotype 1). In this ongoing Phase IIb trial, Week 4 (W4) data from treatment-naïve patients
showed significantly greater HCV RNA reductions with NM283/pegIFN compared to pegIFN alone (Dieterich, EASL
2006). Here we report longer term results from this trial.
Methods:
Enrolled pts have hepatitis C (HCV-1), HCV RNA ≥5 log10
IU/mL by TaqMan™ PCR, ALT <5 xULN,
compensated liver disease, and no prior treatment. Pts were randomized into 5
treatment groups:
a) pegIFN alone QW to W4, with NM283 added in
W5 (dose ramped from 400 to 800 mg/d), with both drugs continued thereafter
b) NM283 200 mg/d + pegIFN
c) NM283 ramped 400 to 800 mg/d in 1st
wk, + pegIFN
d) NM283 800 mg/d, + pegIFN
e) NM283 800 mg/d, + pegIFN
PegIFN-α2a is dosed 180 μg
QW starting Day 8 (Groups A-D) or Day 1 (Group E). Serum HCV RNA is assessed by
the TaqMan™ real-time PCR assay, with PCR-nondetectability reported here at the historically-used Amplicor™ PCR quantitation limit
and the TaqMan™ limit.
Results:
The study is fully enrolled with 173 pts. Final W12 HCV RNA
results and interim W24 results (with data presently available for 96/173 pts)
are shown below. Compared to prior W4 results, W12 and W24 data show a
convergence of anti-HCV efficacy across treatment groups due to continued viral
clearance to PCR-nondetectable levels in most pts in
all groups. Early virologic response (≥2 log10 drop in HCV RNA at W12)
was observed in 82-92% of pts. Treatment B (with NM283 200 mg/d) has been
generally well-tolerated. GI side effects were more common and were
occasionally severe at the 800 mg/d NM283 dosing level (arms C-E). After a
protocol amendment pts are continuing NM283 at the 200 or 400 mg/d levels (with
weekly pegIFN) with improved tolerance to date. Final
W24 results will be available at the meeting.
Conclusions:
At doses as low as 200 mg/d, valopicitabine plus pegIFN markedly suppresses viremia in treatment-naïve
patients with HCV-1 infection. By W24, most patients have achieved PCR-nondetectable HCV RNA by the sensitive TaqMan
assay.
|
|
Mean ↓ from
Baseline |
Amplicor™ negative |
TaqMan™ negative |
|||||
|
Treatment Group |
n |
Week 12 |
n |
Week 24 |
Week 12 |
Week 24 |
Week 12 |
Week 24 |
|
A |
34 |
-4.11 |
18 |
-4.50 |
68 |
83 |
59 |
61 |
|
B |
34 |
-3.86 |
20 |
-4.44 |
68 |
75 |
44 |
70 |
|
C |
34 |
-4.11 |
20 |
-4.48 |
74 |
80 |
44 |
65 |
|
D |
36 |
-4.57 |
18 |
-4.71 |
81 |
83 |
67 |
72 |
|
E |
35 |
-4.04 |
20 |
-4.06 |
69 |
60 |
54 |
50 |
M.
L. Shiffman; E. Schiff; P. Pockros;
G. Burgess; J. Spanton; J. McHutchison.
Background:
Increased rates of hepatocyte apoptosis and activated caspases have been observed in viral hepatitis. Elevated
serum levels of ALT and AST reflect hepatocellular damage. This study examined
the efficacy and safety of the pancaspase inhibitor
PF-03491390 in reducing elevated ALT and AST in pts with chronic HCV infection.
Methods:
In this multicenter,
placebo-controlled, double-blind, parallel-group, dose-ranging study 204 pts
with documented chronic HCV and liver fibrosis were randomized to receive
either placebo or PF-03491390 5mg, 25mg, or 50mg orally bid for 12 weeks. If
ALT and AST were still elevated at week (Wk) 10, the dose of study drug was
doubled to Wk 12. Co-primary endpoints were absolute change from baseline in
ALT and AST at Wk 10, the last visit of the initial randomized dose.
Results:
Median absolute ALT and AST values decreased from Baseline to
Wk 10 in all treatment groups; reductions were statistically significant
compared to placebo at all doses studied (Table 1; P < 0.0001).
Highly significant reductions in serum AST and ALT were
observed for each dose of PF-03491390 versus placebo. Reductions in ALT and AST
were observed starting at Wk 1, were maintained throughout the study, and
returned to baseline levels when PF-03491390 was discontinued. The degree of
reductions in AST and ALT were similar across all treatment doses.
Most adverse events were of mild or moderate severity; the
most frequently reported treatment-emergent events were headache in 24 pts and
fatigue in 22 pts. No change in mean log HCV RNA was observed in any of the treatment
groups.
Conclusions:
PF-03491390 was well tolerated and effectively reduced ALT
and AST in pts with chronic HCV hepatitis during a 12-Wk treatment period.
Further randomized trials are necessary to determine whether PF-03491390 may influence
liver histology in patients with liver fibrosis.
Table
1. PF-03491390 Reduced Serum AST and ALT by Wk 10 in the Intent-to-Treat
Population
|
|
Placebo |
PF-03491390
|
PF-03491390
|
PF-03491390
|
|
No. pts |
51 |
55 |
50 |
48 |
|
Baseline AST IU/L |
60 |
69 |
58 |
73 |
|
AST IU/L |
-2 |
-17† |
-23† |
-25† |
|
Baseline ALT IU/L |
101 |
103 |
98 |
115 |
|
ALT IU/L |
-2 |
-34† |
-41† |
-49† |
†P < 0.0001 versus placebo
I.
M. Jacobson; R. Ghalib; E. Lawitz;
B. Freilich; S. C. Gordon; P. Kwo;
T. R. Riley; D. Bright; M. L. Morris; M. Al-Adhami;
J. L. Himes; F. E. Massari; J. G. McHutchison.
Background:
CPG 10101 (CPG) is an investigational Toll-like receptor 9
(TLR9) agonist that activates plasmacytoid dendritic cells and B cells directly and NK/NKT cells
indirectly, initiating and enhancing antiviral mechanisms mediated by both
innate (antiviral cytokines including IFN-α) and adaptive immunity.
Methods:
74 HCV genotype 1 infected treatment-refractory Relapsed
Responders (RR) who previously received ≥24 weeks PEG-IFN+RBV treatment
were randomized and treated initially for 12 weeks in 1 of 5 arms: P+R, C+P+R,
C+P, C+R, or C alone [CPG (C)=0.2 mg/kg SC weekly; PEG-IFN (P)=1.5 μg/kg SC weekly; RBV (R)=800-1400 mg PO daily].
Patients in CPG-containing arms who achieved ≥2 log10 reduction at Week
12 (EVR) were eligible to continue treatment for up to 48 weeks. All P+R
patients were eligible to roll-over to C+P+R after completing the initial 12
weeks of treatment, regardless of viral level.
Results:
The mean log10 HCV RNA reduction at Week 12 was
significantly greater in the C+P+R arm vs. P+R. A greater proportion of
patients receiving C+P+R achieved RVR, EVR, and HCV RNA undetectability
(<50 IU/mL) than those receiving P+R.
In CPG-containing arms 20 of 24 EVR patients elected to
continue. An additional 2 C+P+R and 2 C+P patients became undetectable during
continuation (2 C+P+R & 1 C+P undetectable patient stopped prior to Week
24). On Treatment Responses (OTR; undetectable at Week 24) were achieved by 7
of 14 (50%) C+P+R and 3 of 16 (19%) C+P patients. 14 of 15 P+R patients rolled
over to treatment with C+P+R. During rollover treatment 5 patients who remained
positive throughout 12 weeks of P+R treatment became undetectable. 2 rollover
patients achieved a first reduction of >2 log10 HCV RNA. AEs
were predominantly of mild/moderate intensity and consisted of headache,
flu-like symptoms, nausea, and injection site reactions.
Conclusions:
In this study CPG improved early antiviral activity of P+R in
treatment-refractory (RR) patients. CPG in combination with P±R was generally
well tolerated. Continuation treatment with C+P±R has led to additional HCV RNA
undetectable responses beyond Week 12. Patients will be followed for End of
Treatment Response (ETR) and Sustained Viral Response (SVR).