Monday Poster Sessions, October 30, 2006

Presidential Plenary Session

 

 

92. Combination of Telaprevir (VX-950) and Peg-IFN-alfa Suppresses Both Wild-type Virus and Resistance Variants in HCV Genotype 1-Infected Patients in a 14-day Phase 1b study.

T. Kieffer; C. Sarrazin; J. Miller; S. Traver; Y. Zhou; D. Bartels; B. Hanzelka; U. Mh; 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.

 


93. Valopicitabine (NM283) plus Peg-Interferon in Treatment-Nave Hepatitis C Patients with HCV Genotype-1 Infection: HCV RNA Clearance During 24 Weeks of Treatment.

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-nave 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-nave patients with HCV-1 infection. By W24, most patients have achieved PCR-nondetectable HCV RNA by the sensitive TaqMan assay.

 

 

Mean from Baseline
(log10 IU/mL)

Amplicor negative
<600 IU/mL (%)

TaqMan negative
<20 IU/mL (%)

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

 


95. PF-03491390, (formerly IDN-6556) a Pancaspase Inhibitor, is Well-Tolerated and Effectively Reduces Raised Aminotransferases (ALT and AST) in Chronic Active Hepatitis C (HCV) Patients (pts).

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
5 mg bid

PF-03491390
25 mg bid

PF-03491390
50 mg bid

No. pts

51

55

50

48

Baseline AST IU/L

60

69

58

73

AST IU/L
Reduction from Baseline at Wk 10

-2

-17

-23

-25

Baseline ALT IU/L

101

103

98

115

ALT IU/L
Reduction from Baseline at Wk 10

-2

-34

-41

-49

P < 0.0001 versus placebo


96. Early Viral Response and On Treatment Response to CPG 10101 (ACTILONTM), in combination with pegylated interferon and/or ribavirin, in chronic HCV genotype 1 infected patients with prior relapse response.

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 PR was generally well tolerated. Continuation treatment with C+PR 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).