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

Transcription

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

2 Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 1) Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease and Transplantation Columbia University College of Physicians & Surgeons New York Presbyterian New York, NY

3 Part 1. An overview of selected all oral HCV direct acting antiviral (DAA) therapy presentations from:

4 Program Disclosure This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. This program is supported by educational grants from Janssen and Vertex Pharmaceuticals.

5 Educational Objectives Describe development goals for future therapies for the treatment of chronic hepatitis C Assess potential efficacy and safety of new orally effective compounds currently under investigation for the treatment of chronic hepatitis C Recognize how new compounds might fit into the future treatment armamentarium for chronic hepatitis C

6 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

7 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

8 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

9 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

10 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

11 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

12 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

13 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

14 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)

15 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

16 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

17 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

18 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

19 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%)

20 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

21 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

22 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

23 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

24 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

25 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

26 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

27 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

28 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

29 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

30 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

31 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

32 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

33 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

34 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

35 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

36 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

37 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

38 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

39 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

40 Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 2)

41 Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 2) Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease and Transplantation Columbia University College of Physicians & Surgeons New York Presbyterian New York, NY

42 PegIFN and RBV remain vital components of HCV therapy-- selected presentations from:

43 Program Disclosure This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. This program is supported by educational grants from Janssen and Vertex Pharmaceuticals.

44 Educational Objectives Assess safety profile of peginterferon lambda-1a compared to peginterferon alfa-2a in patients with HCV Evaluate efficacy and safety of direct acting antiviral agents in combination with peginterferon and ribavirin in difficult-to-treat patients with chronic hepatitis C Recognize continuing importance of peginterferon and ribavirin in combination with direct acting antiviral agents in the treatment of chronic hepatitis C

45 Goals for Hepatitis C Therapy Compared to PegIFN α/rbv, new treatment regimens for chronic hepatitis C should offer: Improved efficacy Efficacy in all patient types including previously treated patients, cirrhotic and black patients Orally effective regimens, IFN free Shorter treatment durations Improved side-effect profiles

46 Selected Antivirals for the Treatment of Chronic Hepatitis C, 2012 New agents covered in this presentation, all in Phase 3 trials Compound Sponsor Activity Peginterferon Lambda-1a Sofosbuvir (GS-7977) Simeprevir (TMC435) Bristol-Myers Squibb Gilead Janssen Type III interferon immune modulator Uridine nucleotide analog NS5B polymerase inhibitor NS3/4A protease inhibitor

47 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Peginterferon Lambda 1a (Lambda) Compared to Peginterferon Alfa 2a (Alfa) in Treatment Naïve Patients With HCV Genotypes (GT) 1 or 4: SVR24 Results From EMERGE Phase 2b Muir AJ, Hillson JL, Gray TE, Xu D, Ishak L, Freeman JA, Fontana D, Horga A, Lopez-Talavera JC Abstract 214, AASLD 2012

48 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Methods 407 non-cirrhotic, treatment-naïve patients infected with HCV GT1: N=384 GT4: N=23 Treatment: Lambda: 120, 180, or 240 μg weekly Alfa: 180 μg weekly All patients received daily ribavirin Treatment duration: 48 weeks Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

49 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Efficacy HCV RNA <LLOQ (% patients) RVR (Week 4) cevr (Week 12 ETR (Week 48) SVR24 (Week 72) Lambda 120 ug + RBV (N=98) Lambda 180 ug + RBV (N=102) Lambda 240 ug + RBV (N=104) Alfa 180 ug + RBV (N=103) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

50 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients HCV RNA concentration over time Lambda 120 g Lambda 180 g Lambda 240 g Alfa-2a 180 g Lambda is asociated with a faster decline in HCV RNA levels Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

51 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Safety Results: Adverse Events Adverse Events n (%) Lambda 120 μg N=98 Lambda 180 μg N=102 Lambda 240 μg N=104 Alfa 180 μg N=103 Serious adverse events 6 (6.1) 3 (2.9) 9 (8.7) 7 (6.8) IFN dose reductions 6 (6.1) 8 (7.8) 76 (73.1) 29 (28.2) RBV dose held/reduced 11 (11.2) 11 (10.8) 12 (11.5) 34 (33.0) Flu-like symptoms (pyrexia, chills, or pain) Musculoskeletal (arthralgia, myalgia, or back pain) 17 (17.3) 13 (12.7) 8 (7.7) 47 (45.6) 21 (21.4) 16 (15.7) 22 (21.2) 48 (46.6) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

52 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Safety Results: Laboratory Values Laboratory Abnormalities n (%) Hemoglobin <10 g/dl or >3.4 g/dl below baseline Lambda 120 μg N=98 Lambda 180 μg N=102 Lambda 240 μg N=104 Alfa 180 μg N=103 27/97 (27.8) 23/101 (22.8) 19/102 (18.6) 64/103 (62.1) Neutrophils <1000/mm 3 1/97 (1.0) 2/101 (2.0) 1/102 (1.0) 44/103 (42.7) Platelets <100,000/mm 3 0 2/101 (2.0) 0 20/103 (19.4) ALT >5xULN 1/98 (1.0) 1/101 (1.0) 10/102 (9.8) 4/103 (3.9) Direct bilirubin >1.2 mg/dl 0 5/101 (5.0) 13/102 (12.7) 2/103 (1.9) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

53 PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Conclusions Compared to Alfa, treatment with Lambda is associated with comparable efficacy in non-cirrhotic patients chronically infected with HCV GT1 or 4 Patients treated with Lambda experienced less hematologic toxicity and fewer musculoskeletal and flulike symptoms Improved safety profile supports further evaluation of Lambda in combination with direct-acting antiviral agents Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

54 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Once Daily Sofosbuvir (GS-7977) plus PEG/RBV: High Early Response Rates Are Maintained During Post-Treatment Follow-Up In Treatment-Naïve Patients With HCV Genotype 1, 4, and 6 Infection in the ATOMIC Study Hassanein T, Lawitz E, Crespo I, Davis M, DeMicco MP, Nelson DR, Bernstein DE, Afdhal N, Jacobson IM, Vierling JM, Gordon SC, Anderson J, Hyland RH, Hindes R, Symonds WT, Albanis E, Arora S, Kowdley KV Abstract 230, AASLD 2012

55 ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Study Design Day 1 Wk 12 Wk 24 Group A N=52 SOF + PEG + RBV GT1 Group B N=125 SOF + PEG + RBV GT1, 4, 6 Group C N=155 SOF + PEG + RBV SOF (n=75) SOF + RBV (n=75) GT1 Non-cirrhotic, treatment-naive patients with with genotype 1 were randomized 1:2:3 into open-label arms *Of the 125 patients enrolled in Arm B, 11 were genotype 4 and 5 were genotype 6 Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

56 ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Efficacy overall Patients with HCV RNA <LOD (%) Week 4 EOT SVR4 SVR12 SOF+PEG+RBV 12 Wks SOF+PEG+RBV 24 Wks SOF+PEG+RBV Wks Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

57 ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Efficacy in Genotype 4 and 6 Patients with HCV RNA <LOD (%) Week 4 EOT SVR4 SVR12 GT4 (n=11) SOF+PEG+RBV 24 Wks GT6 (n=5) SOF+PEG+RBV 24 Wks Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

58 ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Conclusions Sofosbuvir 400 mg once daily + PEG/RBV for 12 weeks appears to be safe and highly effective for the treatment of patients with HCV genotype 1 12 weeks of sofosbuvir + PEG/RBV was as effective as 24 weeks of therapy in patients with HCV genotype 1 24 weeks of sofosbuvir 400 mg once daily + PEG/RBV appears to be highly effective in HCV genotype 4 and 6 Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

59 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Efficacy and Tolerability of TMC mg Once Daily with Peginterferonα-2a and Ribavirin for Treatment of HCV Genotype 1 Infection in Patients with Metavir Score F3 and F4 (Pillar and Aspire Trials) Poordad F, Fried MW, Zeuzem S, Ferenci P, Lenz O, Sinha R, Callewaert K, Peeters M, Beumont M Abstract 83, AASLD 2012

60 PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Study Design PILLAR: Treatment-naïve patients (including F3) SMV + PR Pbo + PR PR Post-therapy FU SMV + PR PR Post-therapy FU Pbo + PR PR Post-therapy FU RGT in SMV arms ASPIRE: Treatment-experienced patients (prior relapsers, partial and null responders including F3 and F4) SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Poordad F et al. Hepatology 2012; 56(Suppl S1):233A Post-therapy FU Post-therapy FU 75 mg, n= mg, n=77 75 mg, n= mg, n=79 Control, n= mg, n= mg, n= mg, n= mg, n= mg, n= mg, n=65 Control, n= Weeks

61 PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy Placebo/ PR Simeprevir 150 mg/pr SVR24 (%) 5/7 15/19 1/23 38/68 0/10 24/39 PILLAR treatmentnaïve: F3 Poordad F et al. Hepatology 2012; 56(Suppl S1):233A ASPIRE treatmentexperienced: F3/F4 pooled ASPIRE treatmentexperienced: F4 only

62 PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy: Response-guided therapy* in treatment naïve F3 patients 84% (16/19) met RGT* criteria and ended treatment at week 24 SVR24 (%) Simeprevir 150 mg/pr *Response-guided therapy (RGT) criteria in simeprevir arms: End treatment at wk 24 if HCV RNA <25 IU/mL at wk 4 and undetectable at wks 12, 16 and 20; all other patients continued PR up to wk 48 15/16 PILLAR patients who met RGT Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

63 PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy: Treatment-experienced SVR 24 by prior response to PegIFN/RBV in F3/F4 patients SVR24 (%) 0/10 17/26 1/10 14/21 0/3 17/21 31% (4/13) null responders with cirrhosis (F4) achieved SVR24 Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

64 PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Conclusions Excellent SVR24 rates were obtained with simeprevir 150 mg combined with PegIFN/RBV in HCV genotype 1-infected, treatment naïve and - experienced patients Majority of treatment-naive patients were eligible for 24 week treatment duration and achieved >90% SVR24 F3/F4 null responders achieved 33% SVR24 Simeprevir/PegIFN/RBV has a favorable overall safety and tolerability profile Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

65 Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Safety and Tolerability of TMC435 in Combination with Peginterferon α-2a and Ribavirin for Treatment of HCV Genotype 1 Infection in Treatment-Naïve and -Experienced patients (PILLAR and ASPIRE Trials) Fried MW, Poordad F, Zeuzem S, Ferenci P, Lenz O, Ouwerkerk-Mahadevan S, Peeters M, Sinha R, Beumont M Abstract 769, AASLD 2012

66 PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and-experienced HCV 1 Patients Study Design PILLAR: Treatment-naïve patients (including F3) SMV + PR Pbo + PR PR Post-therapy FU SMV + PR PR Post-therapy FU Pbo + PR PR Post-therapy FU RGT in SMV arms ASPIRE: Treatment-experienced patients (prior relapsers, partial and null responders including F3 and F4) SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU Post-therapy FU 75 mg, n= mg, n=77 75 mg, n= mg, n=79 Control, n= mg, n= mg, n= mg, n= mg, n= mg, n= mg, n=65 Control, n= Weeks Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

67 PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in hemoglobin over study period* Mean SE of Actual Values of Hgb (g/dl) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

68 PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in neutrophils over study period* Mean SE of Actual Values of Neutrophils (giga/l) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

69 PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in platelets over study period* Mean SE of Actual Values of Platelets (giga/l) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

70 PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Conclusions Simeprevir 150 mg with PegIFN/RBV was generally well tolerated by both treatment-naïve and treatment-experienced patients in the PILLAR and ASPIRE trials Incidence of AEs, including serious AEs, was comparable between simeprevir-treated patients and PegIFN/RBV control groups There was no difference in mean change over time in hemoglobin, platelets or neutrophils during treatment, between simeprevir and control patients Transporter-mediated bilirubin elevations observed with simeprevir were mild, transient, and reversible Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

71 PegIFN and RBV remain vital components of HCV therapy Summary Improved safety profile supports further evaluation of PegIFN Lambda in combination with direct-acting antiviral agents for the treatment of chronic hepatitis C Sofosbuvir 400 mg once daily + PEG/RBV for 12 weeks appears to be safe and highly effective for the treatment of patients with HCV genotype 1; 24 weeks of sofosbuvir 400 mg once daily + PEG/RBV appears to be highly effective in HCV genotype 4 and 6

72 PegIFN and RBV remain vital components of HCV therapy Summary (cont) Excellent SVR24 rates were obtained with simeprevir 150 mg combined with PegIFN/RBV in HCV genotype 1- infected, treatment naïve and -experienced patients; majority of treatment-naive patients were eligible for 24 week treatment duration and achieved >90% SVR24 PegIFN and RBV when combined with DAA agents will continue to be important components of the HCV treatment armamentarium To treat now or to wait optimal decision-making requires knowledge of current developments