1. NS5A and polymerase inhibitors Mark Sulkowski, MD Professor of Medicine Johns Hopkins University Baltimore Maryland 21212

2. Case 57 yo woman with genotype 1a and bridging fibrosis –PROVE-1 study – treated with TVR x 12 wks and 48 weeks PR –Viral relapse Treatment options?

3. The Goal of Combination Regimens B C Prevention of emergent resistance (pre-existing or de novo) + + A Profound suppression of broad range of viral variants, including pre-existing variants

4. Polymerase Inhibitors Non-nucleoside –VX-222 –ANA-598 –ABT-072; ABT-033 –GS-9190 Nucleos(t)ide analogue –PSI (GS)-7977 –Mericitabine (RG7128)

5. ZENITH Study: VX-222 + Telaprevir + PegIFN Alfa-2a + RBV in Chronic HCV Phase 2b Treatment-naive Genotype 1 HCV RNA >5 log 10 IU/mL No cirrhosis (nonblack: 89%) Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14. Week 0 12 24* 36* (n=18) Weight-based ribavirin dosing (1000-1200 mg). *Patients undetectable HCV RNA at weeks 2 and 8 discontinue treatment at week 12; patients with detectable HCV RNA at week 2 or 8 started PegIFN + RBV at week 12 (until 24 weeks of PegIFN + RBV are received). (n=29) (n=30) PegIFN + RBV* (n=29) VX-222 (100 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* VX-222 (400 mg bid) + Telaprevir (1125 mg bid) PegIFN + RBV* VX-222 (100 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV VX-222 (400 mg bid) + Telaprevir (1125 mg bid) + PegIFN + RBV Dual Regimens Terminated Quad Regimens (stratified by genotype 1a/1b)

6. ZENITH Study: Virologic Response HCV RNA Undetectable Week 24 (n=29/30) SVR24 (12 total weeks of treatment) (n=11/15) Patients (%) 83% 90% VX-222 100 mg + telaprevir + PegIFN + RBV VX-222 400 mg + telaprevir + PegIFN + RBV 93% 82% 83% 87% Nelson DR, et al. Hepatology. 2011;54(supp):1435A. Abstract LB-14. SVR12 (24 total weeks of treatment) (n=18/15)

7. Treatment-naïve, non-cirrhotic, age ≥18 years HCV RNA >50,000 IU/mL Allowed concurrent methadone use Stratified by HCV genotype and IL28B genotype Randomized 1:1:1:1 into IFN-sparing or IFN-free PSI-7977 + RBV PSI-7977 + RBV + Peg - IFN PSI-7977 + RBV PSI-7977 +RBV + Peg-IFN PSI-7977 + RBV PSI-7977 + RBV + Peg-IFN n=10 SVR12 n=10 4 8 Wk 0 12 24 PSI-7977 ELECTRON: Study Design for HCV GT2/3 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

8. Time Wk PSI-7977 RBV 12 weeks PEG PSI-7977 RBV 8 weeks PEG PSI-7977 RBV 4 weeks PEG PSI-7977 RBV NO PEG n%<LODn n n 29/11827/8888/9898/1080 411/1110010/101009/910010/10100 811/1110010/101009/910010/10100 1211/11 100 10/10 100 9/9 100 10/10 100 SVR4 11/1110010/101009/910010/10100 SVR8 11/1110010/101009/910010/10100 SVR12 11/11 100 10/10 100 9/9 100 10/10 100 SVR24 6/6 100 5/5 100 5/5 100 4/4 100 PSI-7977 ELECTRON 100% concordance of SVR12 with SVR24 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

9. Assay LLOD 15 IU/mL PSI-7977 ELECTRON Ribavirin may decrease relapse PSI-7977 monotherapy arm (n=10) No on-treatment viral breakthroughs or resistance 6/10 subjects achieved SVR4 4/10 subjects had viral relapse w/o ribavirin PSI-7977/RBV PSI-7977 Monotherapy Combined IFN Arms Time (Days) 027142128 Mean HCV RNA (Log 10 IU/mL) 0 1 2 3 4 5 6 7 Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.

10. NS5A: Replication Complex Inhibitors Daclatasvir – phase 3 Others in phase 2 –Abbott, ABT-267 –Gilead, GS-5885

11. BMS NS5A + PEG / RBV PDR (protocol-defined response): HCV RNA <LLQ (25 IU/mL) at week 4 and undetectable (<10 IU/mL) at week 10. 20 mg BMS-790052 + peg-alfa/RBV (n=180) 60 mg BMS-790052 + peg-alfa/RBV (n=180) 20 mg BMS-790052 + peg-alfa/RBV 60 mg BMS-790052 + peg-alfa/RBV Week 12 Interim Efficacy Analysis and Re-randomization Placebo + peg-alfa/RBV Weeks 1-12Weeks 13-24 Week 4 RNAWeek 10 RNA NO YES NO YES Follow- Up alfa/RBV Peg-alfa/RBV Placebo + peg-alfa/RBV Follow-up Placebo + peg-alfa/RBV Follow-up Placebo + peg-alfa/RBV (n=60) Placebo + peg-alfa/RBV Peg- alfa/RBV Week 24 Interim Safety Analysis PDRPDR Follow-up from Weeks 24 or 48 Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

12. Virologic Responses Through Week 12 in Patients With Genotype 1 Infection LLQ, lower limit of quantitation = 25 IU/mL Undetectable < 10 IU/mL HCV RNA <LLQ and Detectable HCV RNA Undetectable 54 14 60 25 57 19 15 9 78 7 75 9 43 10 0 20 30 40 50 60 70 80 90 100 20 mg + peg- alfa/RBV 60 mg + peg- alfa/RBV Placebo + peg- alfa/RBV 20 mg + peg- alfa/RBV 60 mg + peg- alfa/RBV Placebo + peg- alfa/RBV 20 mg + peg- alfa/RBV 60 mg + peg- alfa/RBV Placebo + peg- alfa/RBV Week 4Weeks 4 and 12Week 12 Percentage of Patients 85 76 24 84 53 1471467214714672n =14714672 Hezode C, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 277.

13. Dual Oral vs Quad Therapy: BMS-790052 + BMS-650032 ± PR Phase 2a study; N=21; 19 with CT/TT IL28B genotype. BMS-790052=NS5A replication complex inhibitor; BMS-650032=NS3 PI BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID) (n=11) BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID) + PR (n=10) Follow-up x 48 weeks 24-week treatment Post treatment: Week 24: SVR24 Group A Group B Lok As et al. New Engl J Med 2012

14. Dual Therapy Group: Resistance Variants in Patients with Viral Breakthrough Viral breakthrough in 6 of 11 pts: All G1a; no resistance variants detected at baseline NS3 protease and NS5A resistance variants detected after viral breakthrough Role of emerging variants confirmed by phenotypic analysis –NS3:30- to 525-fold resistance –NS5A:3400- to >330,000-fold resistance Patient #123456* Week tested24781012 NS3 protease variants (%) D168Y (87) D168A (13) R155K (100)D168Y (100)D168E (100)R155K (100)D168V NS5A variants (%) Y93N (100)L31V (100)Q30R (100) L31M (100) Q30R (76) L31V (100) Y93C (17) Q30R (45) L31V (77) H58P (39) Y93C (16) Y93N (13) Q30R L31V H54Y Y93C 0 2 4681012 0 2 4 6 8 1000 IU/mL LOQ LOD HCV RNA (log 10 IU/mL) Week 1 2 3 4 5 6 BL *Clonal analysis not performed on patient 6 McPhee F, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation 63.

15. Present study: dual therapy in 10 G1b null responders, non-cirrhotic Treated for 24 weeks Dose of BMS 650032 reduced from 600mg bid to 200mg bid secondary to ALT elevations No viral breakthrough and no effect of pre Existing viral mutants 2 SAE’s: 1 hyperbilirubineia, 1 pyrexia SVR (%) Chayama K, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. LB-4 Dual oral combination therapy with the NS5A inhibitor BMS-790052 and the NS3 PI BMS-650032 achieved 90% SVR24 in HCV G1b-infected null responders Confirmation of high SVR in G1b patients with IFN- free regimen despite history of null response to PR. Need for high resistance barrier component of IFN-free regimens may be subtype-dependent (less in G1b than G1a).

16. Antiviral activity in all HCV genotypes No selection of resistance All-oral combination regimen Short treatment duration QD (or BID) dosing Excellent safety and tolerability Applicable in difficult-to-treat populations:  Transplant  Coinfection  End-stage renal disease, etc. Applicable in difficult-to-treat populations:  Transplant  Coinfection  End-stage renal disease, etc. Combination therapy