April 11-15, 2007 Barcelona, Spain *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an educational grant from of the 2007 Annual Meeting of the European Association for the Study of the Liver* Clinical Updates in HCV Treatment CCO Independent Conference Coverage

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment About These Slides Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.  Users are encouraged to include these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent.  These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.  We are grateful to Ira M. Jacobson, MD, with the Weill Medical College of Cornell University in New York, New York, for aiding in the content development of these slides.

Novel Protease Inhibitors for Hepatitis C

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Telaprevir 750 mg every 8 hrs + Peg-IFN alfa-2a + RBV (n = 80) Peg-IFN alfa-2a + RBV (n = 80) Peg-IFN alfa-2a + RBV (n = 80) Telaprevir 750 mg every 8 hrs + Peg-IFN alfa-2a + RBV (n = 80) Telaprevir 750 mg every 8 hrs + Peg-IFN alfa-2a + RBV (n = 20) Peg-IFN alfa-2a + RBV (n = 80) McHutchison JG, et al. EASL Late Breaker 786. Randomized, phase II trial (N = 260 planned) Week 12: Interim Analysis * *Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. † Patients must achieve undetectable HCV RNA at Week 4 (< 10 IU/mL) and at last test before stopping therapy at 12 or 24 weeks. Week 24Week 48 † Week Week Follow-up PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients  Current analysis: data on all patients through Week 12 of treatment –Also patients in 12-week treatment arm who made it to Week 20 of follow-up † 24-Week Follow-up 24-Week Follow-up 24-Week Follow-up Placebo + Peg-IFN alfa-2a + RBV (n = 80)

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients  High rates of RVR (Week 4) and EVR (Week 12)  Virologic breakthrough rates –Telaprevir: 7% (12/175) –Controls: 3% (2/80)  Follow-up for 12-week treatment arm –67% (6/9) patients who achieved Week 4 RVR and discontinued treatment after 12 weeks were HCV RNA negative 20 weeks posttreatment McHutchison JG, et al. EASL Late Breaker 786. P <.001 Virologic Response Rates (HCV RNA < 10 IU/mL) Week 4 Patients (%) Week 12 Telaprevir + peg-IFN + RBV (pooled; n = 175 dosed) Peg-IFN + RBV (n = 75 dosed) P <.001

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients  Discontinuation due to adverse events through Week 12 –Control arm: n = 2 (3%) – Telaprevir: n = 19 (11%) –Rash most common cause for telaprevir discontinuation (n = 7) –Median time to onset of severe rash: 62 days McHutchison JG, et al. EASL Late Breaker 786. Adverse Event, %Telaprevir + Peg-IFN + RBV (Pooled; n = 175) Peg-IFN + RBV (n = 75) Severe rash60 Nausea5030  Severe 22 Pruritus3720 Diarrhea3421 Grade 1 anemia4029 Grade 2 anemia 179

Novel Polymerase Inhibitors for Hepatitis C

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Valopicitabine in Treatment-Naive HCV Genotype 1 Patients Lawitz E, et al. EASL Abstract 14. Treatment- naive patients with HCV GT 1 (N = 172*) Week Study Amendment* Week 1Week 4 Peg-IFN alfa-2a alone Week 48 Peg-IFN alfa-2a 180 µg/week + Valopicitabine 800 mg/day (n = 34) No TX Valopicitabine 200 mg/day Peg-IFN alfa-2a 180 µg/week + Valopicitabine 200 mg/day (n = 34) Valopicitabine ramped from mg/day Peg-IFN alfa-2a 180 µg/week + Valopicitabine 800 mg/day (n = 34) Valopicitabine 800 mg/day Peg-IFN alfa-2a 180 µg/week + Valopicitabine 800 mg/day (n = 36) Peg-IFN alfa-2a 180 µg/week + Valopicitabine 800 mg/day (n = 35) 24-Week Follow-up *Week 12 GI-related adverse events resulted in reduction of valopicitabine dose in arms receiving 800 mg; these patients were randomly reassigned 1:1 to valopicitabine 200 mg or 400 mg + peg-IFN for the remainder. Week 72

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Valopicitabine in Treatment-Naive HCV Genotype 1 Patients (cont’d)  800-mg groups pooled for efficacy analysis  Mean HCV RNA decrease at Week 48 –Valopicitabine 200 mg + peg-IFN alfa-2a: IU/mL –Valopicitabine 800 mg + peg-IFN alfa-2: IU/mL Lawitz E, et al. EASL Abstract 14. Valopicitabine 200 mg + peg-IFN alfa-2a (n = 34) Valopicitabine 800 mg + peg-IFN alfa-2a (n = 139) Week 12Week 24Week 48 Patients (%) Proportion of Patients With Undetectable HCV RNA (< 20 IU/mL)* *Dropout = treatment failure.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Valopicitabine in Treatment-Naive HCV Genotype 1 Patients (cont’d)  Discontinuation rates, adverse events tended to be higher with 800-mg dose –7 treatment-related serious adverse events  Incidence of valopicitabine-related GI adverse events dose dependent Lawitz E, et al. EASL Abstract 14. Outcome, %Valopicitabine 200 mg + Peg-IFN alfa-2a (n = 34) Valopicitabine 800 mg + Peg-IFN alfa-2a (n = 139) Treatment discontinuation3855 Diarrhea3844 Nausea6581 Vomiting3853 Headache2730 Fatigue4450 Depression2123 Flu-like symptoms1829

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBV  Phase IIb study of valopicitabine ± peginterferon Afdhal NH, et al. EASL Abstract 6. Week 1Week 48Week 72 *Data pooled from two 800-mg groups in current analysis. GT 1 previous nonresponders with HCV RNA ≥ 10 5 IU/mL, ALT < 5 x ULN, and compensated liver disease (N = 190) Valopicitabine 800 mg/day monotherapy Val 400 mg/day Peg-IFN + Valopicitabine 400 mg/day Val 400 → 800 mg/day Val 800 mg/day Follow-up No TreatmentPeg-IFN + RBV mg Peg-IFN + Valopicitabine 800 mg* (n = 21) (n = 42) (n = 43)

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBV Afdhal NH, et al. EASL Abstract 6. Week 48 Mean Reduction in HCV RNAVirologic Response Rates (< 50 IU/mL) Week 48SVR Patients (%) Valopicitabine 400 mg/day + Peg-IFN Peg-IFN + RBV Valopicitabine 800 mg/day + Peg-IFN (pooled data) Mean log 10 Change

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBV Outcome, %Valopicitabine 800 mg/day + Peg-IFN (n = 82) Valopicitabine 400 mg/day + Peg-IFN (n = 41) Peg-IFN + RBV (n = 34) Discontinued treatment  Due to adverse event23203 Nausea Fatigue Vomiting66499 Diarrhea Headache Depression Insomnia Neutropenia Afdhal NH, et al. EASL Abstract 6.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment HCV Peg-IFN in Treatment-Naive Hepatitis C Patients Villano SA, et al. EASL Abstract 50. Treatment-naive chronic hepatitis C patients without advanced or decompensated liver disease (N = 65) HCV mg BID + Peginterferon alfa-2b 1.5 µg/kg (n = 12) Day 14: End of Treatment Day 1: Peg-IFN Dose 1 Day 7: Peg-IFN Dose 2 HCV mg BID + Peginterferon alfa-2b 1.5 µg/kg (n = 10) HCV mg BID + Peginterferon alfa-2b 1.5 µg/kg (n = 12) Placebo + Peginterferon alfa-2b 1.5 µg/kg (n = 19) HCV mg BID + Peginterferon alfa-2b 1.5 µg/kg (n = 12) Day 28 Follow-up

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment HCV-796 in Treatment-Naive Hepatitis C Patients Villano SA, et al. EASL Abstract 50. *< 50 IU/mL. Peg-IFN (n = 15) 100 mg HCV Peg-IFN (n = 10) 250 mg HCV Peg-IFN (n = 9) 1000 mg HCV Peg-IFN (n = 12) 500 mg HCV Peg-IFN (n = 10) Day 14 Change in HCV RNA From Baseline ≥ 2 Log Change≥ 3 Log ChangeHCV RNA Negative* Patients (%)

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment HCV-796 in Treatment-Naive Hepatitis C Patients (cont’d) Villano SA, et al. EASL Abstract 50. Mean log 10 Change: Day 14 Genotype 1Genotype Non-1 Peg-IFN 100 mg HCV Peg-IFN 250 mg HCV Peg-IFN 500 mg HCV Peg-IFN 1000 mg HCV-796 +Peg-IFN Peg-IFN 100 mg HCV Peg-IFN 250 mg HCV Peg-IFN 500 mg HCV Peg-IFN 1000 mg HCV Peg-IFN

Novel Small Molecule Therapies for Hepatitis C

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Efficacy of DEBIO-025 in HIV/HCV-Coinfected Patients  DEBIO-025: oral small molecule inhibitor of cyclophilin  1200 mg twice daily for 14 days (n = 16) vs placebo (n = 3) in treatment-naive HIV/HCV-coinfected patients  Biphasic viral decay kinetics demonstrated  Effective across GT 1, 3, 4  No rebounds noted Herrmann E, et al. EASL Abstract Time (Days) DEBIO-025Placebo HCV RNA (log 10 copies/mL) Treatment Figure used with permission from Dr. Eva Herrmann.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment NS4A Antagonist ACH-806 in HCV Genotype 1–Infected Patients  ACH mg twice daily for 5 days (n = 8) vs placebo (n = 2) in naive or experienced patients Pottage JC, et al. EASL Abstract 783. Figure used with permission from John C. Pottage, Jr., MD. ACH-806 (n = 8) Placebo (n = 2) Mean Change in HCV RNA log 10 (IU/mL) Study Day 020 Treatment

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment NS4A Antagonist ACH-806 in HCV Genotype 1–Infected Patients (cont’d)  4 patients had > 1 log 10 IU/mL reduction in HCV RNA –Mean reduction: 0.91 log 10 IU/mL  6 individuals had increases in serum creatinine –Mean Day 3 increase: 0.43 mg/dL –Mean Day 5 increase: 0.49 mg/dL  Drug development halted due to renal toxicity  Proof of concept demonstrated Pottage JC, et al. EASL Abstract 783.

Novel Interferons for Hepatitis C

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Albinterferon Alfa-2b/RBV Treatment in Genotype 2/3 Patients  Interim analysis of multicenter, randomized, open-label, phase II trial –Albinterferon alfa-2b recombinant interferon fused with human serum albumin Treatment-naive patients chronically infected with HCV genotype 2/3 (N = 43) Albinterferon alfa-2b 1500 µg every 2 weeks subcutaneously + Ribavirin 800 mg/day (n = 21) Albinterferon alfa-2b 1500 µg every 4 weeks subcutaneously + Ribavirin 800 mg/day (n = 22) Week 24 Stratification by HCV genotype (2 or 3) and HCV RNA (< vs ≥ 800,000 IU/mL) Follow-up planned for 24 additional weeks; interim follow-up performed at Week 36 Bain VG, et al. EASL Abstract 9.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Albinterferon Alfa-2b/RBV Treatment in Genotype 2/3 Patients (cont’d) Bain VG, et al. EASL Abstract 9. Alb-IFN Q2W + RBV (n = 21)Alb-IFN Q4W + RBV (n = 22) Week 4*Week 12*Week 24 † (EOT) Week 36 † (Post-Tx) Undetectable HCV RNA (%) Week 36 Outcomes According to Genotype *Limit of detection, 43 IU/mL. † Limit of detection, 10 IU/mL. GT 2 † GT 3 † Virologic Outcomes Undetectable HCV RNA (%) Figures used with permission from Vincent G. Bain, MD, FRCP(C).

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Albinterferon-Based Therapy vs Standard of Care Zeuzem S, et al. EASL Abstract 779. Interferon-naive, genotype 1, chronic hepatitis C patients (N = 458) Albinterferon alfa-2b 900 µg Q2W + Weight-Based Ribavirin mg/day (n = 118) Albinterferon alfa-2b 1200 µg Q2W + Weight-Based Ribavirin mg/day (n = 110) Week 48 Stratification by HCV RNA (< vs ≥ 800,000 copies/mL) and body mass index (< vs ≥ 25) Albinterferon alfa-2b 1200 µg Q4W + Weight-Based Ribavirin mg/day (n = 116) Peginterferon alfa-2a 180 µg/week + Weight-Based Ribavirin mg/day (n = 114) Week Week Follow-up Week 60: Current Interim Analysis

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Albinterferon-Based Therapy vs Standard of Care (cont’d) Figure used with permission from Stefan Zeuzem, MD Week 4*Week 12*End of Treatment † Week 12 Posttreatment † Patients (%) Alb-IFN 900 μg Q2W Alb-IFN 1200 μg Q2W Alb-IFN 1200 μg Q4W Peg-IFN 180 µg/week *< 43 IU/mL. † < 10 IU/mL. Proportion of Patients With Undetectable HCV RNA Zeuzem S, et al. EASL Abstract 779.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Albinterferon-Based Therapy vs Standard of Care (cont’d)  Quality of life significantly less impaired for patients on albinterferon 1200 µg every 4 weeks vs those on peginterferon at Weeks 12, 24, and 48 (P <.05) Zeuzem S, et al. EASL Abstract 779. Safety and Dose Reductions, % Alb-IFN 900 µg Q2W + RBV (n = 118) Alb-IFN 1200 µg Q2W + RBV (n = 110) Alb-IFN 1200 µg Q4W + RBV (n = 116) Peg-IFN 180 µg Q1W + RBV (n = 114) Severe adverse events Treatment discontinuation due to adverse event Interferon dose reduction  Due to adverse event  Due to lab abnormality

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Recombinant IFN Omega for Treatment-Naive GT 1 Patients  Randomized, open-label, phase II trial Novozhenov V, et al. EASL Abstract 11. Treatment-naive patients with genotype 1 chronic HCV infection (N = 102) Interferon Omega 25 µg/day (n = 35) Interferon Omega 25 µg/day + Ribavirin 1000/1200 mg BID (n = 67) Week 48: ETR Week 12: Subjects must demonstrate a > 2 log 10 reduction in HCV RNA level* to continue Week 72: SVR *Limit of detection < 600 IU/mL. Follow-up

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Recombinant IFN Omega for Treatment-Naive GT 1 Patients (cont’d) Novozhenov V, et al. EASL Abstract EVRHCV RNA- Week 12ETR Patients (%) Virologic Response Rates 6 36 SVR P =.014 P =.001 Omega alone (n = 35)Omega + ribavirin (n = 67)

Ribavirin Analogues for Hepatitis C

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C  Multicenter, active-control, parallel group, double-blind phase III study Marcellin P, et al. EASL Abstract 10. 2:1 Randomization Taribavirin 600 mg BID + Peginterferon alfa (n = 644) Ribavirin 1000/1200 mg BID + Peginterferon alfa (n = 318) 24 or 48 Weeks of Treatment* 24 Weeks of Follow-up Treatment-naive chronic hepatitis C patients (N = 962) *According to genotype.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C (cont’d) Marcellin P, et al. EASL Abstract 10. SVR Rate*, %Ribavirin + Peginterferon (n = 318) Taribavirin + Peginterferon (n = 644) Overall5540 Genotype 1 patients4427 Genotype 2/3 patients8167 *HCV RNA < 39 IU/mL.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Marcellin P, et al. EASL Abstract 10.  Higher rate of anemia in ribavirin vs taribavirin group –22% vs 6%, respectively (P <.001)  Post hoc subgroup analysis: higher SVR rates in those receiving > 15 mg/kg taribavirin –Increase in anemia rate in those receiving > 15 mg/kg of taribavirin Ribavirin Taribavirin Dose, mg/kg ≤ 13> 13-15> 15-18> 18 Patients, n SVR, % Anemia, % VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C (cont’d)

Using Virologic Response to Determine Treatment Duration

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Treatment length determined Treatment-naive patients with HCV GT 1 infection (N = 694) Peg-IFN + RBV for 48 weeks (n = 235) Peg-IFN + RBV for 72 weeks (n = 52) Peg-IFN + RBV for 24 weeks (n = 122) Peg-IFN + RBV for 48 weeks (n = 128) Week 24Week 48Week 72Week 96 Follow-up Mangia A, et al. EASL Abstract 7. Extended Treatment in Genotype 1 Slow Responder Patients Standard Tx regardless of response HCV RNA negative at Week 4 HCV RNA negative at Week 8 HCV RNA positive at Week 8 Week 8 Follow-up

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Mangia A, et al. EASL Abstract 7. Extended Treatment in Genotype 1 Slow Responder Patients (cont’d) Virologic Outcomes in Week 12 Responders (< 50 IU/mL) 72-week treatment Patients (%) End of Treatment Response SVR P = week treatment

Predictors of SVR

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Week 4 Ribavirin Concentration as a Predictor of SVR  Week 4 ribavirin concentrations correlated with SVR in 22 patients –Cutoff of 2 mg/L significantly associated with SVR Maynard M, et al. EASL Abstract 619. SVR Rate* (%) Week 4 Ribavirin (mg/L) < > 2.43 Week 4 Ribavirin (mg/L) SVR Rate* (%) ≤ 2> P =.05 P =.03 n = *Measured through quantitative PCR.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Relationship Between Renal Function and SVR in Hepatitis C Patients  German multicenter, open-label, observational study  Treatment-naive HCV patients (N = 10,326) screened –Initiated peginterferon plus ribavirin with complete GFR data sets (n = 1615) –Patients stratified into 2 groups –Normal GFR: > 90 mL/min/1.73 m 2 (n = 1498) –Low GFR: mL/min/1.73 m 2 (n = 107) –10 patients with GFR < 60 mL/min/1.73 m 2 excluded from analysis  GFR differed according to sex, age, and HCV genotype but not according to weight or BMI Zehnter E, et al. EASL Abstract 656.

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Relationship Between Renal Function and SVR in Hepatitis C Patients (cont’d)  GFR affected response rates in genotype 1,4 but not genotype 2,3 patients  Anemia more common among patients with low GFR Zehnter E, et al. EASL Abstract 656. Normal GFR (> 90; n = 1498)Low GFR (> 60-90; n = 107) Patients (%) Anemia Patients (%) n = Genotype 1/4Genotype 2/3Total Sustained Virologic Response n = 241 Figures used with permission from Elmar Zehnter, MD. Total

Summary and Conclusions

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Conclusions Protease inhibitors  High rates of rapid response with telaprevir plus peginterferon/ribavirin in naive patients based on interim data –High sustained response rates in those undergoing 12 weeks of therapy following Week 4 RVR –Treatment-limiting adverse effects include rash, GI problems Polymerase inhibitors  Valopicitabine 200 mg/day plus peginterferon alfa-2a resulted in end of treatment response in one half of treatment-naive genotype 1 patients  Poor SVR rates with valopicitabine/peginterferon retreatment –May be due to high discontinuation rates, lack of ribavirin use

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Conclusions (cont’d) Polymerase inhibitors (cont’d)  Viral suppression in ~ one third of treatment-naive patients receiving HCV-796/peginterferon alfa-2b Small molecule therapies  Novel NS4A antagonist ACH-806 displayed strong viral suppression –Drug halted due to renal toxicity  DEBIO-025 effective across genotypes in 14-day treatment trial

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Conclusions (cont’d) Novel interferons in interferon-naive patients  Week 12 posttreatment sustained response rates comparable to standard of care with albinterferon every-4-week dosing –Significantly better quality of life  High Week 12 posttreatment sustained response rates with albinterferon in genotype 2/3 patients –Best rates in genotype 3 individuals  36% SVR rate with interferon omega plus ribavirin in genotype 1 patients

clinicaloptions.com/hep EASL 2007: Clinical Updates in HCV Treatment Conclusions (cont’d) Ribavirin analogues  Taribavirin associated with significantly lower SVR rates than ribavirin, except at higher doses Determining optimal treatment duration  Extending treatment to Week 72 in slow responders improved SVR rates vs 48 weeks of treatment Predictors of SVR  Week 4 serum ribavirin concentration > 2 mg/L associated with higher SVR rates  Poor renal function associated with lower SVR rates in genotype 1/4 patients

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