Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 1)

Transcription

1 Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 1)

2 Goals for Hepatitis C Therapy Compared to PegIFN/RBV, new products should offer: Improved efficacy Efficacy in all patient types including previously treated patients, cirrhotic and black patients Orally effective regimen, IFN free Shorter treatment duration Improved side-effect profile

3 Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012 Compound Sponsor Activity ABT-267 Abbott NS5A inhibitor ABT-333 Abbott Non-nucleoside NS5B polymerase inhibitor ABT-450 Abbott NS3/4A protease inhibitor Faldaprevir (BI201335) Boehringer Ingelheim NS3/4A protease inhibitor BI Boehringer Ingelheim Non-nucleoside NS5B polymerase inhibitor

4 Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012 (cont) Compound Sponsor Activity Asunaprevir (BMS ) Daclatasvir (BMS ) Bristol-Myers Squibb Bristol-Myers Squibb NS3 protease inhibitor NS5A replication complex inhibitor BMS Bristol-Myers Squibb Non-nucleoside NS5B polymerase inhibitor Sofosbuvir (GS-7977) Gilead Uridine nucleotide analog NS5B polymerase inhibitor GS-5885 Gilead NS5A protein inhibitor Not all-inclusive, but indicates drugs covered in this presentation

5 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Interferon (IFN)-Free Combination Treatment with the HCV NS3/4A Protease Inhibitor BI and the Non-Nucleoside NS5B Inhibitor BI ± Ribavirin (R): Final Results of SOUND-C2 and Predictors of Response Zeuzem S, Soriano V, Asselah T, Bronowicki J-P, Lohse AW, Mullhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts SK, Gane EJ, Stern JO, Vinisko R, Herichova I, Boecher WO, Mensa FJ Abstract 232, AASLD 2012

6 SOUND-C2 Trial Update: BI BI RBV Five arm study that evaluated different doses and durations in regimens with faldaprevir (PI) and BI (non-nuc) with or without RBV Durations: 16, 28 or 40 weeks BID vs TID Randomization was stratified by genotype (1a vs 1b) and IL28B 9% of patients had cirrhosis SVR12 ranged between 52% to 69% in RBV-containing arms and 39% without RBV SVR in cirrhotics is 54%* IL28B CC, genotype 1b and female gender were favorably associated with SVR12 Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract 84, AASLD 2012

7 SOUND-C2 Trial Update: BI BI RBV Study Design Phase IIb, multicenter, open-label, randomized 1:1:1:1:1 Treatment-naive patients with chronic HCV GT-1 Stratified by GT-1 subtype (1a vs. 1b) and IL28B (CC vs. non-cc) Compensated cirrhosis included years of age HCV RNA >100,000 IU/mL Stopping rule: HCV RNA detectable between weeks 6 and 8 Primary endpoint: SVR12 Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

8 SOUND-C2 Trial Update: BI BI RBV Objective To present final SVR12 data for all arms and an analysis of baseline parameters that were associated with SVR in the SOUND-C2 Trial; SOUND-C2 investigated the combination of Faldaprevir (NS3/4A protease inhibitor; formerly BI201335) and BI (non-nucleoside NS5B inhibitor) in treatment-naïve patients with genotype 1 HCV Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

9 SOUND-C2 Trial Update: Faldaprevir + BI RBV Study Design n=81 Faldaprevir 120 mg QD +B I mg TID + RBV Follow-up n=80 Faldaprevir 120 mg QD + BI TID + RBV Follow-up n=77 Faldaprevir 120 mg QD + BI TID + RBV Follow-up n=78 Faldaprevir 120 mg QD + BI BID + RBV Follow-up n=46 Faldaprevir 120 mg QD + BI TID, no RBV Follow-up Day 1 Wk 16 Wk 28 Wk 40 Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

10 SOUND-C2 Trial Update: Faldaprevir + BI RBV Primary endpoint: SVR12 (ITT and per protocol) 100 ITT SVR12 (%) % 69% 69% 59% 59% 52% 72% 69% 44% 39% Per Protocol 20 0 BI Dosing TID TID TID BID TID Duration (weeks) RBV Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

11 SOUND-C2 Trial Update: Faldaprevir + BI RBV SVR12 according to HCV subtype (ITT) % GT-1a 80 75% 69% GT-1b SVR12 (%) % 44% 47% 56% 43% 57% 20 11% 0 BI Dosing TID TID TID BID TID Duration (weeks) RBV Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

12 SOUND-C2 Trial Update: Faldaprevir + BI RBV SVR12 according to IL28B genotype (ITT) SVR12 (%) % 67% 67% 63% 64% 57% 58% 55% 48% 33% Non-CC CC 20 0 BI Dosing TID TID TID BID TID Duration (weeks) RBV Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

13 SOUND-C2 Trial Update: Faldaprevir + BI RBV Moderate AEs (Occurring in >10% of patients in any treatment arm) TID 16W (n=81) TID 28W (n=80) TID 40W (n=77) BID 28W (n=78) TID 28W -NR (n=46) Moderate AEs 27 (33) 32 (40) 34 (44) 28 (36) 19 (39) Nausea 2 (3) 10 (13) 5 (7) 6 (8) 2 (4) Vomiting 4 (5) 10 (13) 3 (4) 3 (4) 2 (4) Asthenia 6 (7) 10 (13) 15 (20) 8 (10) 0 Fatigue 2 (3) 1 (1) 8 (10) 3 (4) 2 (4) Rash 4 (5) 2 (3) 2 (3) 0 7 (15) Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

14 SOUND-C2 Trial Update: Faldaprevir + BI RBV Severe AEs (Occurring in 2 patients) TID 16W (n=81) TID 28W (n=80) TID 40W (n=77) BID 28W (n=78) TID 28W -NR (n=46) Severe AEs 1 (1) 8 (10) 12 (16) 9 (12) 4 (9) Anemia 0 1 (1) 0 1 (1) 0 Dehydration 0 1 (1) 0 1 (1) 0 Vomiting (5) 0 1 (2) Rash 1 (1) 1 (1) 3 (4) 0 1 (1) Photosensitivity reaction 0 1 (1) 2 (3) 0 0 Asthenia (1) 2 (3) 0 Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

15 SOUND-C2 Trial Update: Faldaprevir + BI RBV D/C due to AEs (Occurring in >5% of patients in any treatment group) TID 16W (n=81) TID 28W (n=80) TID 40W (n=77) BID 28W (n=78) TID 28W -NR (n=46) D/C due to AEs 4 (5) 10 (13) 19 (25) 6 (8) 5 (11) Vomiting 1 (1) 2 (3) 5 (6) 0 0 Photosensitivity 2 (2) 0 4 (5) 0 0 Rash 2 (2) 3 (4) 5 (6) 0 4 (9) Asthenia (8) 0 0 Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

16 SOUND-C2 Trial Update: Faldaprevir + BI RBV Conclusions Faldaprevir + BI RBV achieved SVR rates of up to 69% in the present study which included patients with compensated cirrhosis BI BID had the most favorable tolerability profile with a low rate of discontinuation and no moderate or severe skin reactions GT-1a patients had lower SVR12 rates than GT-1b patients, possible due to the lower activity of BI in this population RBV remains a necessary component of treatment Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

17 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Once Daily Sofosbuvir (GS-7977) Plus Ribavirin in Patients with HCV Genotypes 1, 2, and 3: The ELECTRON Trial Gane EJ, Stedman CA, Hyland RH, Sorensen RD, Symonds WT, Hindes R, Berrey MM Abstract 229, AASLD 2012

18 ELECTRON Trial Objective To evaluate sofosbuvir (SOF; formerly GS-7977), a uridine nucleotide analog, plus ribavirin (RBV) in additional ELECTRON study arms: SOF + RBV in treatment-naïve genotype 1 patients SOF + RBV in null responder genotype 1 patients SOF + RBV in treatment experienced (Prior null response, breakthrough, or relapse) in genotype 2/3 patients To determine feasibility of shorter duration or reduced dose of RBV in treatment naive genotype 2/3 patients To evaluate the efficacy and safety of adding GS-5885, an NS5A inhibitor, to SOF + RBV in treatment naïve and null responder genotype 1 patients Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A Press release. November 10, Gilead Sciences, Inc., Foster City, CA. Available at

19 ELECTRON Trial Update: Sofosbuvir (GS-7997) + Ribavirin in Genotypes 2 and 3 HCV Treatment Population Results SOF + RBV, 12 wks GT 2/3 Treatmentexperienced 68% (17/25) SVR12 SOF + RBV, 12 wks GT 2/3 Treatment-naïve 100% (11/11) SVR24 SOF + RBV, 8 wks GT 2/3 Treatment-naïve 64% (16/25) SVR12 SOF + RBV (800 mg), 12 wks GT 2/3 Treatment-naïve 60% (6/10) SVR8 Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A Press release. November 10, Gilead Sciences, Inc., Foster City, CA. Available at

20 ELECTRON Trial Update: Sofosbuvir + RBV vs. SOF + GS RBV in Genotype 1 HCV Patients with HCV RNA <LOD over time, n/n (%) SOF + RBV SOF + GS RBV Treatment- Naïve (n=25) *Includes one patient who stopped all treatment for SAE at week 8 Data collection ongoing Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A Null Responder (n=10) Treatment- Naïve (n=25) Null Responder (n=9) Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0) Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44) Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89) EOT (Week 12) 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100) SVR4 22/25 (88) 1/10 (10) 25/25 (100)* 3/3 (100) SVR12 21/25 (84) 1/10 (10)

21 ELECTRON Trial Update: Sofosbuvir + RBV vs. Sofosbuvir + GS RBV in Genotype 1 HCV Adverse Events, n (%) Treatment- Naïve (n=25) *SAEs considered unrelated to SOF Stopped treatment at week 8 at time of partial colectomy for diverticular perforation Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A SOF + RBV Null Responder (n=10) SOF + GS RBV Treatment- Naïve (n=25) Null Responder (n=9) SAEs* 1 (4) 0 2 (8) 0 AEs that led to discontinuation (4) 0 Grade 2 AEs 10 (40) 3 (30) 12 (48) 2 (22) Anemia 0 1 (10) 5 (20) 0 Headache 1 (4) 0 1 (4) 0 Depression 0 1 (10) 2 (8) 0 Ligament sprain 1 (4) 1 (10) 0 0

22 ELECTRON Trial Update: Sofosbuvir + RBV vs. Sofosbuvir + GS RBV in Genotype 1 HCV Grade 3 and 4 Laboratory Abnormalities, n (%) Treatment- Naïve (n=25) SOF + RBV Null Responder (n=10) SOF + GS RBV Treatment- Naïve (n=25) Null Responder (n=9) Grade 3 11 (44) 4 (40) 13 (52) 2 (22) Grade ALT 1 (4) Total bilirubin 1 (4) Hemoglobin 3 (12) 3 (30) 5 (20) 2 (22) Prothrombin time 1 (4) 0 2 (8) 0 Urine occult blood 5 (20) 2 (20) 9 (36) 0 Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

23 ELECTRON Trial Summary: Genotype 1 HCV SOF + RBV for 12 weeks provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders Addition of GS-5885 increased efficacy of SOF + RBV 100% SVR4 in treatment-naïve patients 3/3 SVR4 in null responders No additional safety/tolerability issues detected Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

24 ELECTRON Trial Summary: Genotype 2 or 3 HCV SOF + RBV for 12 weeks appears to be a safe and effective regimen for both treatment-naïve and previously treated patients Durations of less than 12 weeks or reduced RBV dose may adversely impact treatment efficacy Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

25 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA High Efficacy Of GS-7977 (SOF) In Combination With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis From The SPARE Trial Osinusi A, Heytens L, Lee Y-J, Bon D, Shivakumar B, Nelson A, Meissner EG, Kohli A, Barrett L, Proschan M, Silk R, Kwan R, Herrmann E, Sneller M, Teferi G, Talwani R, Symonds WT, Polis MA, Masur H, McHutchison JG, Fauci AS, Kottilil S Abstract LB-4, AASLD 2012

26 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Objective: To assess the safety, tolerability, and efficacy of SOF in combination with weight-based (full) or low dose ribavirin (RBV) for 24 weeks in HCV monoinfected, genotype 1, treatment-naive subjects SOF is a specific nucleotide analog HCV polymerase inhibitor Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

27 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Study Design Sixty HCV genotype 1, treatment-naive subjects Part 1: Stages 0-2 fibrosis Part 2: All stages (including Child Pugh Class A) 24 weeks Part 1 SOF + RBV mg N=10 SVR 12 Part 2 SOF + RBV mg N=25 SOF + RBV 600 mg N=25 SVR 12 SVR 12 Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

28 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Baseline Demographics SOF + Full dose RBV (N=10) SOF + Full dose RBV (N=25) Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012 SOF + Low dose RBV (N=25) Median age (range) 54 (30-65) 54 (30-65) 55 (26-78) Male sex (%) 4 (40%) 20 (80%) 14 (56%) Genotype 1a (%) 6 (60%) 20 (80%) 16 (64%) African American (%) 9 (90%) 18 (72%) 23 (92%) Median BMI (range) 26 (22-43) 28 (22-44) 30 (19-47) IL28B CT/TT (%) 6 (67%) 21 (84%) 21 (84%) Median HCV RNA log (IQR) 6.85 ( ) 6.16 ( ) 6.05 ( ) Advanced fibrosis (%) 0 6 (24%) 7 (28%)

29 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Treatment Response: Full dose RBV (Part 1; N=10) % 90% 90% 90% 90% ITT HCV RNA <LLOQ (%) Week 4 Week 12 ETR SVR4 SVR12 mitt: 100% SVR12 (1 drop out at week 3) Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

30 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Treatment Response: Part 2 Full dose RBV (N=25); 1 drop out at wk % 96% 96% 88% 96% 88% Low dose RBV (N=25) 3 drop outs by wk 8 ITT HCV RNA <LLOQ (%) % 56% 20 0 Week 4 Week 12 ETR SVR4 mitt: 75 % SVR4 for full dose RBV; 64% for low dose RBV Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

31 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Grade 2 Adverse Events Grade 2 AEs, n (%) GS Full dose RBV (N=35) GS Low dose RBV (N=25) Headache 0 2 (8%) Nausea 1 (3%) 1 (4%) Fatigue 1 (3%) 0 Rash 2 (6%) 1 (4%) Pruritus 1 (3%) 1 (4%) Myalgia 0 2 (8%) Depression 1 (3%) 0 Neutropenia 0 1 (4%) Hyperbilirubinemia 4 (11%) 1 (4%) Decreased Hgb 7 (20%) 1 (4%) No Grade 4 events; two Grade 3 events (nausea [1]; hyperbilirubinemia [1]) Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

32 SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype 1 HCV Patients Conclusions: In this inner city population of HCV genotype 1 treatment-naïve patients, SOF + RBV administered for 24 weeks resulted in: Full dose RBV: SVR4 of 77% Low dose RBV: SVR4 of 56% There were no safety signals or drug-related discontinuations in this study Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

33 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naïve Patients Chronically Infected With HCV Genotype 1, 2, or 3 Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson IM, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Eley T, Wind-Rotolo M, Huang S-P, Gao M, McPhee F, Sherman D, Hindes R, Symonds WT, Pasquinelli C, Grasela DM Abstract LB-2, AASLD 2012

34 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Objective: To evaluate the efficacy and safety of daclatasvir (DCV; BMS ) plus sofosbuvir (SOF; GS- 7977) with or without RBV 24 weeks in treatment-naïve patients infected with HCV GT1 (1a/1b), 2, or 3 12 weeks in treatment-naïve patients infected with GT1 (1a/1b) DCV is an NS5A replication complex inhibitor; SOF is a nucleotide analogue NS5B polymerase inhibitor Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

35 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Study Design Randomized 44 GT1 and 44 GT2 or 3 HCV, non-cirrhotic patients 1:1:1 to: SOF for 7 days, then DCV+SOF for 23 weeks DCV+SOF for 24 weeks DCV+SOF+RBV for 24 weeks An additional 82 GT1 patients were randomized 1:1 to DCV+SOF RBV for 12 weeks Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

36 Study Design: GT 1a/1b Week 24 SVR 4 SVR 12 SVR 24 SVR 48 n = 15 Group A: SOF 400 mg QD x 7d, then DCV 60 mg QD + SOF 400 mg QD Follow-up n = 14 Group C: DCV 60 mg QD + SOF 400 mg QD Follow-up n = 15 Group E: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up n = 41 Group G: DCV 60 mg QD + SOF 400 mg QD Follow-Up n = 41 Group H: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-Up Week 12 SVR 4 SVR 48 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

37 HCV RNA < LLOQ (% patients) Virologic Response is Maintained at PT Week 24 (GT1a/1b; 24-Week Treatment Groups) A: SOF LI + DCV C: DCV + SOF E: DCV + SOF + RBV 20 n = Week 4 EOT SVR 4 SVR 12 SVR 24 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

38 HCV RNA < LLOQ (% patients) Virologic Response During and After Treatment: 12 Week Treatment Groups (GT 1a/1b) G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk) n = Week 4 EOT SVR 4 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

39 Virologic Response is Maintained at PT Week 24 (GT 2 or 3; 24-Week Treatment Groups) 120 SOF LI + DCV DCV + SOF DCV + SOF + RBV HCV RNA <LLOQ (% patients) Week 4 EOT SVR4 SVR12 SVR24 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

40 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Genotype 1: Virologic Response During and After Treatment, 12- and 24-Week Groups (mitt) HCV RNA <LLOQ (% patients) SOF LI + DCV DCV + SOF DCV + SOF + RBV DCV + SOF (12 wk) DCV + SOF + RBV (12 wk) Week 4 EOT SVR4 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

41 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Genotype 1: Virologic Response During and After Treatment, 24-Week Groups (mitt) SOF LI + DCV DCV + SOF DCV + SOF + RBV HCV RNA <LLOQ (% patients) Week 4 EOT SVR4 SVR12 SVR24 Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

42 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Safety On-Treatment Patients with event, n (%) Safety Parameters Adverse events in 20% of patient total SOF LI + DCV (N=31) 24-week treatment DCV + SOF (N=28) DCV + SOF + RBV (N=29) 12-week treatment DCV + SOF (N=41) DCV + SOF + RBV (N=41) Grade 3-4 AEs 0 4 (14) 2 (7) 1 (2) 1 (2) Discontinuations due to AEs 0 1 (4) 1 (3) 0 0 SAEs 2 (6) 4 (14) 2 (7) 1 (2) 0 Hgb <9g/dL (grade 3-4) (21) 0 5 (12) Fatigue 9 (29) 14 (50) 9 (31) 16 (39) 13 (12) Headache 5 (16) 8 (29) 11 (38) 14 (34) 9 (22) Nausea 5 (16) 9 (32) 9 (31) 8 (20) 8 (20) Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

43 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Conclusions: DCV + SOF with or without RBV achieved SVR in 93% of patients with HCV genotype 1, 2, or 3 HCV genotype 2 or 3 (N=44) 24-week duration: SVR24=93% of patients HCV genotype 1 (N=126) 12-week duration: SVR4=96% 24-week duration: SVR24=98% Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

44 All-Oral Combination of Daclatasvir Plus Sofosbuvir Ribavirin in Treatment Naïve HCV GT 1, 2, or 3 Conclusions (cont): Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin DCV + SOF with or without ribavirin was generally well tolerated Low hemoglobin was observed only in patients taking ribavirin Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

45 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS Yielded SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, Loustaud-Ratti V, Rustgi VK, Schwartz H, Tatum HA, Marcellin P, Pol S, Thuluvath PJ, Eley T, Wang X, Huang SP, McPhee F, Wind-Rotolo M, Chung E, Pasquinelli C, Grasela DM, Gardiner DF Abstract LB-3, AASLD 2012

46 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV In pilot studies, 24 weeks of DCV + ASV was effective in prior null responders with HCV GT 1b infection In this Phase 2a study with DCV + ASV + BMS , objective was to Enhance virologic responses Improve efficacy in GT 1a Maintain tolerability Shorten treatment duration to 12 weeks DCV is an NS5A replication complex inhibitor, ASV is an NS3 protease inhibitor, and BMS is a selective non-nucleoside NS5B polymerase inhibitor

47 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV Part 1 Group 1 DCV+ASV+BMS mg 12-week follow-up Group 2 DCV+ASV+ BMS mg 12-week follow-up Part 2 Group 3 DCV+ASV+BMS mg 12-week follow-up Additional Follow-up to SVR 48 Group 4 DCV+ASV+ BMS mg 12-week follow-up Study Week Results from Part 1 presented; Part 2 enrolled and ongoing. Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

48 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV: Preliminary Results HCV RNA Endpoints: Group 1, 24-Week Treatment Patients Achieving HCV RNA <LLOQ (%) % 94% 94% N=16 94% 0 Week 4 Week 12 EOT PT4 Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

49 SVR(%) IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV 94%** **One lost to follow up Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

50 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV: Preliminary Results HCV RNA Endpoints: Group 2, 12-Week Treatment Patients Achieving HCV RNA <LLOQ (%) % 88% 100% 94% N=16 94% 0 Week 4 Week 12 EOT SVR4 SVR12 Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

51 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV: Preliminary Results HCV RNA Outcomes HCV Genotype 1a (mitt) % 100% 92% 100% 24 Wk (Group 1) Patients Achieving HCV RNA <LLOQ (%) Wk (Group 2) 20 0 N=12 N=12 N=12 N=12 EOT SVR4 SVR achieved despite predominance of IL28B non-cc genotype Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

52 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV: Preliminary Results Safety: Adverse Events and Laboratory Abnormalities on Treatment Number of Patients (%) 24-Wk Treatment Group 1 N=16 12-Wk Treatment Group 1 N=16 Serious AEs 0 1 (6) AEs leading to discontinuation 0 0 Grade 3-4 AEs 0 1 (6) Grade 3-4 laboratory abnormalities 0 1 (6) AEs in >10% of patients in combined treatment groups Headache 4 (25) 6 (38) Diarrhea 2 (13) 6 (38) Asthenia 2 (13) 3 (19) Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

53 IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Genotype 1 HCV: Preliminary Results Conclusions DCV + ASV + BMS resulted in high rates of SVR after both 12 and 24 weeks of treatment Regimen was generally well tolerated There was no viral breakthrough and no post treatment relapse to date Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

54 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA A 12-Week Interferon-free Treatment Regimen with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naïve Patients and 93% in Prior Null Responders with HCV Genotype1 Infection Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, Everson GT, Kwo PY, Foster GR, Sulkowski MS, Xie W, Pilot-Matias T, Liossis G, Larsen LM, Khatri A, Podsadecki TJ, Bernstein B Abstract LB-1, AASLD 2012

55 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Objective To assess efficacy and safety of several interferon free regimens of ABT-450/r with ABT-267 and/or ABT-333 ribavirin (RBV) ABT-450 is an HCV NS3/4 protease inhibitor that is coadministered with ritonavir (ABT-450/r) and dosed once daily ABT-267 is an NS5A inhibitor that is dosed once daily ABT-333 is a non-nucleoside polymerase inhibitor dosed twice daily Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

56 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV N Study Design ABT-450, ABT-267, ABT-333, RBV ABT-450, ABT-450, ABT-267 ABT-333, RBV ABT-450, ABT-267, ABT-333 RBV ABT-450, ABT-267, ABT-333, RBV ABT-450, ABT-267, ABT-333, RBV wk 0 wk 8 wk 12 wk ABT-450, ABT-267 RBV ABT-450, ABT-267, ABT-333, RBV ABT-450, ABT-267, ABT-333, RBV Treatment Naïve Prior Null Responder Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012 ABT-450/r Dose QD 150/ / /100, 200/ / /100, 150/ /100, 150/ / /100, 150/ /100, 150/100

57 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV SVR12 Rates (ITT) for 8- and 12-week Arms % 85.4% 89.9% 87.3% 97.5% 88.9% 93.3% 80 ITT SVR12 (%) n=80 n=41 n=79 n=79 n=79 n=45 n=45 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT wks 12 wks 12 wks RBV ABT-450 ABT-267 ABT-333 RBV Treatment Naïve Prior Null Responder Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

58 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV ITT SVR12 Rates by HCV Subtype (N=448) a 1b SVR12 (%) ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT wks 12 wks 12 wks RBV ABT-450 ABT-267 ABT-333 RBV Treatment Naïve Prior Null Responder Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

59 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV ITT SVR12 Rates by IL28B Genotype CC non-cc SVR12 (%) ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT wks 12 wks 12 wks RBV ABT-450 ABT-267 ABT-333 RBV Treatment Naïve Prior Null Responder Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

60 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Moderate-to-Severe AEs Possibly or Probably Related to Study Drug with >5% Incidence in Any Arm Treatment-Naïve Patients Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012 Null Responders Duration 8 wks 12 wks 12 wks Regimen ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV Number dosed Any AE, n (%) 20 (25.0) 12 (29.3) 14 (17.7) 10 (12.7) 19 (24.1) 7 (15.6) 11 (24.4) Fatigue 7 (8.8) 2 (4.9) 3 (3.8) 3 (3.8) 2 (2.5) 1 (2.2) 3 (6.7) Headache 3 (3.8) 4 (9.8) 3 (3.8) 0 1 (1.3) 0 1.(2.2) Insomnia 2 (2.5) 1 (2.4) 1 (1.3) 0 4 (5.1) 1 (2.2) 0 Nausea 1 (1,3) 2 (4.9) 1 (1.3) 0 2 (2.5) 0 1 (1.2) Bilirubin increase (1.3) 0 2 (2.5) 0 0

61 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Grade 3-4 Laboratory Abnormalities Occurring in More Than 1 Patient (8- and 12-week arms) Clinical Chemistry Event, n (%) Treatment-Naïve Patients (N=358) Null Responders (N=90) Total bilirubin 2x ULN 24 (6.7) 11 (12.2) ALT >5x ULN, 2x BL value 4 (1.1) 1 (1.1) Triglycerides >504 mg/dl 4 (1.1) 1 (1.1) Alkaline Phosphatase >1.5x ULN 4 (1.1) 0 Creatinine 1.5 mg/dl 4 (1.1) 1 (1.1) Glucose >250 mg/dl 3 (0.8) 1 (1.1) Sodium <130 mg/dl 3 (0.8) 0 Calculated creatinine clearance <50 ml/min 2 (0.6) 1 (1.1) Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

62 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Grade 3-4 Laboratory Abnormalities Occurring in More Than 1 Patient (8- and 12-week arms), cont Hematology Event, n (%) Treatment-Naïve Patients (N=358) Null Responders (N=90) White blood cells >20x10 9 cells/l 4 (1.1) 1 (1.1) Lymphocytes <0.5x10 9 cells/l 4 (1.1) 0 Platelets <10 9 cells/l 2 (0.6) 0 Neutrophils <10 9 cells/l 3 (0.8) 1 (1.1) Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

63 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Safety All DAA combinations studied were well tolerated through 8-12 weeks of treatment Fatigue, headache, insomnia, and nausea were seen most frequently Transient asymptomatic elevation of indirect bilirubin was seen, consistent with the known effect of ABT- 450 on the bilirubin transporter OATP1B1 1% of patients discontinued due to adverse events

64 ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV Conclusions The 12-week 3 DAA + RBV regimens showed the greatest efficacy in both treatment-naive and null responder populations All DAA combinations studied were well tolerated through 8-12 weeks of treatment Phase 3 studies with the 3 DAA combination (with and without RBV) recently initiated Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

65 Emerging Therapies for HCV: Highlights from AASLD 2012 Summary Compared to current treatment regimens for chronic hepatitis C, therapies currently under investigation offer: Improved efficacy Oral effectiveness (IFN free) Shorter treatment durations While most studies are too preliminary for definitive conclusions regarding safety, no unusual safety issues have been identified to date

66 Emerging Therapies for HCV: Highlights from AASLD 2012 Summary As with current IFN-containing treatment regimens, host (IL28B genotype) and virus (genotype 1a/1b) interactions influence treatment outcomes with certain DAA combinations Additional data are needed in difficult-to-treat patient groups (Blacks, cirrhotics, previously treated patients) To treat now or to wait optimal decision-making requires knowledge of current developments