Late Breaking Posters: Monday Nov 3: 8am

HCV Drug pipeline – Vaccines

LB7. Antiviral effects of therapeutic vaccination with naked DNA delivered by in vivo electroporation in patients with chronic hepatitis C.

M. Sällberg; H. M. Diepolder; M. C. Jung; L. Frelin; I. Mathiesen; M. P. Fons; R. W. Hultcrantz; T. Carlsson; O. Weiland

Background:

Clearance of HCV infection correlates with activation of the host T cell response. We therefore developed a T cell vaccine based on a codon-optimized HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter and delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients, approved by the Swedish Medical Products Agency and the local ethics committy is ongoing.

Methods:

A volume of 0,5 mL saline containing ChronVac-C® DNA (Tripep AB, Sweden) was injected at 1 cm depth in the deltoid muscle. This was immediately followed by two 60ms electrical pulses adminstered using a 1,5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). The study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load <800,000 IU/mL were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA. The fourth group will receive the best dose according to results from the first three groups. The study is performed at the Karolinska University Hospital in Stockholm, Sweden, and the immunological analysis is performed by ImmuSystems GmbH, Munich, Germany

Results:

In the 167µg group all patients have completed therapy, no severe side effects appeared, two mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose group all patients have completed therapy, no severe side effects appeared, and two developed HCV-specific T cell responses of longer duration. Simultaneous with the T cell responses, these two patients had reductions in the viral load of up to 0,89log10 and 1,5 log10, respectively. In the third patient no immune response developed and no clear reductions in the viral load were seen. On a group level in the 500 µg dose group, the mean HCV RNA levels at treatment weeks six and eight added together were significantly lower (-0,35log10) as compared the mean HCV RNA levels obtained before therapy start with screening and week zero added together (p<0,05, Mann-Whitney). All patients in the 1500 µg dose group have started therapy and no severe side effects have been recorded.

Conclusions:

These data from the first clinical trial provides a preliminary proof-of-concept for DNA-based therapeutic vaccination against chronic hepatitis C using in vivo electroporation and encourage further clinical development. The data also provides further evidence for the antiviral role of the HCV-specific T cell response.

HCV Drug Pipeline – General

LB8. Safety and antiviral activity of TMC435350 in treatment-naïve genotype 1 HCV-infected patients.

M. P. Manns; H. W. Reesink; C. Moreno; T. Berg; Y. Benhamou; Y. J. Horsmans; G. M. Dusheiko; R. Flisiak; P. Meyvisch; O. Lenz; K. Simmen; R. Verloes

Background:

TMC435350 (TMC435) is an NS3/NS4A protease inhibitor in development for the treatment of hepatitis C virus (HCV) infection.

Methods:

A double blind, placebo-controlled Phase IIa trial is ongoing to assess the antiviral activity, safety, and pharmacokinetics of once-daily (QD) regimens of TMC435 in HCV genotype 1 treatment-naïve patients. Results of the first 28 days of treatment of Cohort 1 (25 or 75mg TMC435 versus placebo) are reported here.

Patients were randomized to receive either 7 days of monotherapy of TMC435 or placebo followed by 21 days triple therapy with TMC435 or placebo, PegIFNα-2a (180 μg once weekly) and ribavirin (RBV; 1000-1200 mg daily) (Panel A); or 28 days of triple therapy with TMC435 or placebo, PegIFNα-2a and RBV (Panel B). After day 28, patients continue on PegIFNα-2a/RBV alone for a total of 24 or 48 weeks at the discretion of the investigator.

Results:

25 patients were enrolled to each Panel of Cohort 1 (N=50). No serious or severe AEs were related to TMC435. There were no safety-related treatment discontinuations, and no dose related safety findings. Most common AEs associated with TMC435 were nausea, diarrhea and headache. There were no clinically relevant mean changes in laboratory parameters, ECGs or vital signs. Steady-state plasma trough levels of TMC435 25mg and 75mg QD represented ~10 and ~30-fold excess above the HCV replicon EC50 value, respectively.

Mean reductions of HCV RNA from baseline at day 7 with TMC435 alone and in triple therapy were 2.63 and 3.47 log10 IU/mL respectively in the 25mg arm, and 3.43 and 4.55 log10 IU/mL in the 75mg arm. In the 75mg 4-week triple therapy arm, no viral breakthrough was observed; 9/9 patients achieved HCV RNA below lower limit of quantification (<25 IU/mL) and 8/9 patients achieved undetectable HCV RNA (<10 IU/mL) at day 28 (RVR=89%).

Conclusion:

TMC435 at doses of 25mg and 75mg QD was well tolerated and demonstrated dose-dependent antiviral activity, both alone and in combination with PegIFNα-2a/RBV. Cohort 2 investigating 200mg QD is ongoing.

HCV Drug Pipeline – Vaccines

LB9. GI5005 Immunotherapy Plus Peg-IFN/Ribavirin In Genotype 1 Chronic Hepatitis C Patients Compared To Peg-IFN/Ribavirin Alone In Naive and Non-Responder Patients; Preliminary RVR and Viral Kinetic Analysis From the GI5005-02 Phase 2 Study.

J. G. McHutchison; E. J. Lawitz; J. M. Vierling; G. T. Everson; I. M. Jacobson; M. L. Shiffman; T. D. Boyer; E. R. Schiff; S. Cruickshank; T. C. Rodell; D. Apelian

Purpose

GI5005 is a whole heat-killed S. cerevisiae immunotherapy expressing high levels of HCV NS3 and Core antigens. GI5005 has been designed to elicit antigen-specific host CD4 and CD8 T-cell responses with the goal of improving the rate of immune clearance of HCV. The GI5005-02 phase 2 study evaluates the efficacy and safety of GI5005 plus peg-IFN/ribavirin (SOC) in subjects with genotype 1 chronic HCV infection.

Methods

Genotype 1 subjects with chronic HCV infection who were treatment naïve or non-responders to prior interferon (IFN) or peginterferon (pegIFN) based therapy were eligible (prior null responders and relapsers were excluded). Patients were randomized 1:1, and stratified by virologic response during their prior course of treatment in this open label trial; Arm 1- GI5005 monotherapy run-in consisting of five weekly followed by 2 monthly subcutaneous (SC) doses of 40YU (1 YU = 10,000,000 yeast) GI-5005 over 12 weeks, followed by triple therapy consisting of monthly 40YU GI-5005 doses plus pegIFN/ribavirin (48 wks in naïve patients, 72 wks in prior non-responders), Arm 2- treatment with SOC alone (without antecedent GI5005 monotherapy).

Results

At this interim analysis 28 of 72 patients have completed the first 4 weeks of triple therapy, with a trend to improved rapid virologic response (RVR defined as HCV RNA < 25IU/mL by week 4) in the triple therapy group; overall (8/28 {29%} vs 9/65 {14%}; p=0.08), naïve (8/17 {47%} vs 9/46 {20%}; p=0.03), and baseline HCV RNA >600,000IU/mL (4/22 {18%} vs 5/60 {8%} p=0.19). There were no RVR responses in prior non-responders in either treatment arm. Second phase viral kinetic slopes (Day8-Day29) showed an advantage for triple therapy compared to SOC in prior IFN non-responders (-1.16 log10/mo. vs -0.88 log10/mo; p=0.02), and patients with HCV RNA >600,000 IU/mL at baseline (-1.92 log10/mo. vs -1.76 log10/mo; p= 0.36). Triple therapy has been well-tolerated to date, with no GI5005 related serious adverse events, dose limiting toxicities or discontinuations due to adverse events.

Conclusion

Triple therapy with GI5005 plus pegIFN/ribavirin was well tolerated and has generated preliminary data indicative of improved RVR rates compared to SOC in naïve patients with chronic genotype 1 HCV. Second phase viral clearance kinetics also indicate an early favorable effect of this strategy in prior IFN non-responders. These data are consistent with the HCV-specific cellular immune responses observed in the GI5005-01 phase 1 trial. This therapeutic approach and the mechanism of action of GI5005 support further investigation and development of combination therapy strategies in chronic HCV infection.

HCV Drug Pipeline – R7128

LB10. Antiviral Activity Of The HCV Nucleoside Polymerase Inhibitor R7128 In HCV Genotype 2 And 3 Prior Non-Responders: Interim Results Of R7128 1500mg BID With PEG-IFN And Ribavirin For 28 Days.

E. J. Gane; M. Rodriguez-Torres; D. R. Nelson; I. M. Jacobson; J. G. McHutchison; L. Jeffers; A. Beard; S. Walker; N. Shulman; W. Symonds; E. Albanis; M. M. Berrey

Background:

Historically, HCV genotype (GT) 2 and 3 prior non-responders have demonstrated poor response rates to re-treatment with PEG-IFN/RBV (SOC). No direct-acting antiviral agent in development has shown significant activity in individuals infected with HCV GT 2/3. R7128 is a potent nucleoside analog inhibitor of HCV polymerase, with activity against HCV GT 2/3 in vitro. When administered at doses of 1000-1500mg BID in combination with SOC for 28 days in treatment-naïve, HCV+ GT 1 patients, R7128 delivered an 85-88% rapid virologic response (RVR). This study was designed to evaluate R7128 with 180µg PEG-IFN and 1000-1200mg RBV for 28 days in patients with HCV GT 2 or 3.

Methods:

25 patients (20 active/5 placebo) with genotype 2 (n=10) or genotype 3 (n=15) who had not previously achieved a sustained virologic response (SVR) with interferon-based therapy were enrolled. Patients received R7128 1500mg BID or placebo along with PEG-IFN/RBV for 28 days, followed by PEG-IFN/RBV alone for a minimum of 20 weeks. All patients were non-cirrhotic and all had been previously treated with at least 12 weeks of interferon-based therapy.

Results:

Antiviral Activity

· 90% RVR was demonstrated in this cohort of treatment failure HCV GT 2 or 3 patients with R7128 + SOC .

· Prior treatment response had no impact upon R7128 + SOC response, RVR was 60% in SOC prior relaspers

· The antiviral activity observed with R7128 + SOC was maintained across genotype 2 and 3; and consistent with in vitro data

· Compared to prior therapy, the addition of R7128 resulted in a more rapid decline in plasma HCV RNA, based upon those subjects with available prior treatment histories

· HCV RNA values in the SOC alone group declined with a -3.7 log 10 change from baseline compared to -5.0 in the R7128 cohort

Summary

· A mean 5.0 log 10 decline in plasma HCV RNA was demonstrated following 28 days of combination therapy with R7128 + SOC in HCV genotype 2 or 3 infected subjects

· Compared to prior treatment responses, R7128 provided additional antiviral activity in these subjects

· R7128 was generally well-tolerated and demonstrated no evidence of acute target organ toxicity

· Serum ALT levels normalized during R7128 therapy in 54% of subjects with elevated ALT at baseline

· Pharmacokinetic data demonstrate that the ‘new’ formulation results in slightly higher plasma exposures compared to the previous formulation.

Conclusions

· R7128 has provided positive proof-of-concept that a direct acting antiviral can deliver additional antiviral potency in an HCV genotype 2 or 3 treatment failure population with an RVR of 90%. Longer term data is needed to determine adequate length of treatment in this population.

· As predicted by in vitro data, R7128 demonstrated similar potency against HCV genotype 2 or 3 compared to a previous study of R7128 again genotype 1 HCV

· The absence of virologic breakthrough reinforces the implications from monotherapy studies that nucleo0side polymerase inhibitors have a high genetic barrier to resistance

· The safety and efficacy of this combination study support further development of R7128 in combination with the standard of care (pegylated interferon and ribavirin) in this difficult to rreat, HCV genotype 2/3 non-responder population and provides appropriate potency and safety to progress to Phase 2b studies to explore optimal treatment duration in HCV genotype 2 or 3 treatment-naive patients.

HCV Drug Pipeline – General

LB11. Antiviral Activity of the HCV Polymerase Inhibitor PF-00868554 Administered as Monotherapy in HCV Genotype 1 Infected Subjects.

J. L. Hammond; M. C. Rosario; F. Wagner; D. Mazur; C. Kantaridis; V. S. Purohit; K. Durham; S. Jagannatha; M. F. DeBruin

Background:

PF-00868554 is a novel, potent, non-nucleoside inhibitor of the HCV polymerase. PF-00868554 inhibits genotype 1a and 1b replicons in vitro, with an overall mean EC50 of 0.059 µM. The safety and tolerability of PF-00868554 has been demonstrated in healthy volunteers administered PF-00868554 up to 300 mg TID for 14 days. The objectives of this study were to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of PF-00868554 in HCV-infected subjects.

Methods:

This was a randomized, double-blind, placebo-controlled, sequential group study. Subjects eligible for participation were those naïve to previous interferon-based HCV therapy and infected with a genotype 1 strain of the virus. Four cohorts of 8 subjects were randomized (6:2) to receive oral doses of PF-00868554 (100, 300 and 450 mg BID and 300 mg TID) or placebo, for 8 days.

Results:

Of the 32 subjects randomized, the majority were male (84%) and Caucasian (97%). Mean baseline HCV RNA levels ranged from 5.8 to 6.1 log10 IU/mL. All doses of PF-00868554 were well tolerated. The most frequently reported all-causality AEs were flatulence, headache, fatigue and nasopharyngitis. All AEs were mild or moderate in severity. There were no dose-limiting AEs, Grade 3 or 4 laboratory abnormalities, withdrawals due to AEs, serious AEs, or deaths. The half life of PF-00868554 in this study ranged from 8 to 12 hours. All doses achieved plasma concentrations that exceeded the median protein binding adjusted in vitro EC50 value for genotype 1 HCV throughout the duration of the dosing interval. The mean maximum reduction (log10) in HCV RNA achieved with PF-00868554 100, 300 or 450 mg BID or 300 mg TID was -0.97 to -2.13, respectively. The mean reduction in HCV RNA at the end of PF-00868554 treatment on Day 8 was -0.68 to -1.95, respectively. HCV RNA decreased rapidly during the first 48 hours of PF-00868554 treatment. Following this first phase of viral suppression, most subjects experienced a plateau or rebound in HCV RNA; however, some subjects’ HCV RNA continued to decline through the completion of dosing on Day 8.

Conclusions:

· Results from this study indicate that PF-00868554 was safe and well tolerated at dose levels 100-450 BID and 300 TID in genotype 1 patients.

· PF-00868554 potently inhibited viral replication in HCV-infected, treatment naive subjects, with mean maximum reductions in HCV RNA ranging from -0.97 to -2.13.

· Results from the present study support the further evaluation of PF-00868554, and a study investigating PF-00868554 in combination with pegylated interferon alpha-2a and ribavirin in treatment naïve subjects is currently underway.

HCV Drug Pipeline – General

LB12. BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: Results from a Proof-of-concept Study.

R. Nettles; C. Chien; E. Chung; A. Persson; M. Gao; M. Belema; N. A. Meanwell; M. p. DeMicco; T. C. Marbury; R. Goldwater; P. Northup; J. Coumbis; W. K. Kraft; M. R. Charlton; J. C. Lopez-Talavera; D. Grasela

BMS-790052 is a first in class and highly selective HCV NS5A inhibitor with in picomolar vitro potency against genotypes 1a and 1b. In a single ascending dose study with healthy subjects, BMS-790052 was shown to be safe, well tolerated, and had a pharmacokinetic profile suggestive of once daily dosing.

Objectives

The objectives of this randomized, double blind, placebo-controlled, single ascending-dose study were to evaluate the safety, tolerability, antiviral effect and pharmacokinetics of BMS-790052 in patients with genotype 1 chronic hepatitis C (CHC). Patients were randomized to receive 1, 10, or 100mg of BMS-790052 or placebo (6 patients per dose; active:placebo=5:1) and could be treatment-naive or experienced men or women, 18 to 49 years of age with HCV RNA ≥105 IU/mL with non-cirrhotic compensated liver disease.

All BMS-790052 single doses were well tolerated and had a safety profile similar to that of placebo. Following oral administration, BMS-790052 was readily absorbed with dose proportional exposures over the studied dose range which were comparable to those observed in a previous study of healthy subjects. The mean terminal half-life of BMS-790052 was approximately 12 hours. The figure below shows the decline in HCV RNA for all doses from time of administration to 144 hours. Mean decline in HCV RNA 24 hours after a single 1, 10 and 100 mg dose of BMS790052 was 1.8 log10 (range 0.18 to 3.0 log10), 3.2 log10 (range 2.9 to 4.0 log10) and 3.3 log10 (range 2.7 to 3.6 log10), respectively. Furthermore, the 100 mg dose resulted in a mean decline of 3.6 log10 (range 3.0 to 4.1 log10) observed at 48 hours after dosing, which was maintained at 144 hours.

BMS-790052 is a potent NS5A inhibitor that produces a robust decline in HCV RNA following a single dose in patients chronically infected with HCV genotype 1. BMS-790052 was safe and well tolerated in single doses of up to 100 mg and has a pharmacokinetic profile that potentially supports once-daily dosing. Multiple dose trials are ongoing.

HCV Drug Pipeline – General

LB13. Results of a Phase I Safety, Tolerability and Pharmacokinetic Study of ANA598, a Non-Nucleoside NS5B Polymerase Inhibitor, in Healthy Volunteers.

M. H. Rahimy; C. A. Crowley; J. L. Freddo; M. V. Sergeeva; B. Golec

Background:

ANA598 is a novel non-nucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 NS5B polymerase in development for the treatment of patients with chronic HCV infection. In vitro studies have shown that ANA598 exhibits potent antiviral activity in genotype 1a and 1b replicon systems with EC50 values of 50 and 3 nM (28 and 1.7 ng/mL) and EC95 values of 500 and 30 nM (280 and 17 ng/mL), respectively. Results from an ongoing single-dose escalation trial in healthy subjects are reported here.

Methods:

A phase I, randomized, double-blind, ascending, single-dose trial is being conducted to evaluate the safety, tolerability and pharmacokinetics of ANA598 capsules. Healthy subjects (18 to 55 years of age) were randomized into treatment cohorts consisting of 6 subjects receiving single ascending oral doses of ANA598 (400, 800, 1400, 2000 mg or 2000 mg-fed) and 2 subjects receiving placebo. An additional cohort received 800 mg twice-daily (BID) for 2 doses. All doses were administered in the fasted state with the exception of the 2000 mg-fed group. Safety and pharmacokinetics were assessed over 7 days following oral administration of capsules or matching placebo.

Results:

ANA598 was well tolerated at all doses administered thus far. There have been no serious adverse events and no withdrawals from the study. All adverse events have been classified as mild, with no apparent dose relationship and no pattern of events within any body system. There have been no clinically significant changes in other safety assessments. Preliminary data analyses indicate that systemic exposure generally increases with increasing dose of ANA598 (Table 1). Both Cmax and AUC increased in subjects who received ANA598 after consuming a high-fat meal. On the basis of preliminary analyses of plasma concentrations, ANA598 exhibits a terminal elimination half-life (t1/2) >24 hours, and the t1/2 is independent of dose.

Conclusion:

The favorable pharmacokinetic and tolerability profiles of ANA598 support QD or BID administration. The results support continued development of ANA598 in patients with chronic HCV infection.

Table 1. Mean (SD) ANA598 plasma concentrations (µg/mL) at 12 and 24 hours after administration

	400 mg	800 mg	1400 mg	2000 mg	2000 mg-fed	800 mg BID
C12	8.9 (3.9)	13.4 (4.0)	11.8 (4.2)	23.9 (11.0)	143.5 (26.3)	17.2 (7.4)
C24	4.8 (2.3)	7.7 (2.4)	6.7 (2.8)	12.0 (5.2)	Pending	Pending

HCV Drug Pipeline - Boceprevir

LB16. HCV SPRINT-1: Boceprevir plus Peginterferon alfa-2b/Ribavirin for Treatment of Genotype 1 Chronic Hepatitis C in Previously Untreated Patients.

P. Kwo; E. J. Lawitz; J. McCone; E. R. Schiff; J. M. Vierling; D. Pound; M. Davis; J. S. Galati; S. C. Gordon; N. Ravendhran; L. Rossaro; F. H. Anderson; I. M. Jacobson; R. Rubin; K. Koury ; E. I. Chaudhri; J. K. Albrecht

Background:

Boceprevir (Boc) is an oral HCV-NS3 protease inhibitor being assessed in combination with peginterferon alfa-2b (P) 1.5 µg/kg/QW and ribavirin (R) for chronic hepatitis C.

Methods:

HCV SPRINT-1 is a Phase 2 study in HCV-1 patients evaluating boceprevir 800 mg TID in three treatment regimens: 1) 4 weeks of P/R 800-1400 mg/d (lead-in) followed by addition of boceprevir to the combination for 24 or 44 weeks (total 28 or 48 weeks); 2) boceprevir in combination with P/R (800-1400 mg/d) for 28 or 48 weeks; 3) boceprevir in combination with P/low-dose R (400-1000 mg/d) for 48 weeks, compared to P (1.5 µg/kg QW)/R (800-1400 mg/d) for 48 weeks. The primary endpoint of the study is sustained virologic response (SVR) at 24 weeks of follow-up (Roche Cobas Taqman: LLD 15 IU/mL).

Results:

595 patients treated: 77% US, 16% Black, 7% cirrhotic, 89% >600,000 IU/mL. Regimens 1, 2 and P/R control results from a planned interim analysis are reported. Addition of boceprevir markedly increased SVR with 28 and 48 regimens compared to P/R control. SVR was higher with a 4-week P/R lead-in for the 48 week regimen, while a decrease in viral breakthrough was observed with both 28 and 48-week lead-in regimens. As with P/R, rapid virologic response (RVR) and early virologic response (EVR) were highly predictive of response with the boceprevir combinations. The most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. Incidence of rash-related AEs was similar in boceprevir-containing regimens and P/R control. Treatment discontinuations due to adverse events were between 9 to 19% for patients in boceprevir arms, compared to 8% in control arm.

Conclusions:

· Boceprevir when combined with P/R is safe for use up to 48 weeks and substantially improves SVR rates with 28 weeks of therapy and can nearly double the SVR compared to the current P/R standard of care (48 weeks) in this trial.

· The use of a 4-week lead-in with P/R prior to the addition of boceprevir appears to reduce the incidence of viral breakthrough regardless of treatment duration and may improve SVR over a 48-week treatment duration.

· Further follow-up of this cohort and a large phase 3 trial examining the role of boceprevir will help define the optimal treatment paradigm for the incorporation of boceprevir to P/R in the treatment of genotype 1 HCV infected individuals.