1. What’s new in HCV genotype 2? Alessandra Mangia S.Giovanni Rotondo,ITALY PARIS HEPATITIS CONFERENCE 2012 30-31 January 2012

2. Key issues Epidemiological background Response rates with Peg/RBV Does IL28B plays any role? New therapeutic approaches

3. 9% 27% Mean rate 8.2% M.Conrberg et al 2010 HCV genotype 2 prevalence in Europe and Canada

4. HCV 2 and tx in Italy G3G4 HCV-4 (n=70) HCV-3 (n=275 HCV-2 (n=478) HCV-1 (n=777) 4.3%17%30%48% HCV genotype distribution in 1604 pts enrolled into the Prophesys study in Italy 5% G1G2 62% 27% 7% Prophesys 2 Final analysis

5. Peg-IFN-  + ribavirin: incidence of treatment failure Peg-IFN-  2a + ribavirin 1 Peg-IFN-  2b + ribavirin 3 54% 24% Genotype 1Genotypes 2/3 58% 48% 18% 16% Peg-IFN-  2a + ribavirin 2 1. Fried MW, et al. N Engl J Med 2002;347:975–982 2. Hadziyannis S, et al. Ann Intern Med 2004;40:346–355 3. Manns M, et al. Lancet 2001;358:958–965 Peg-IFN: peginterferon

6. Demographic characteristics of Italian pts with HCV 2/3 evaluated in the interim analysis of the WRITE study HCV 3 (n=303) HCV 2 (n=200) P value Mean age (years) 44.256.50.001 Male gender71%46%0.001 Fibrosis stage 420.5%10.5%0.003 Blood transfusion13%6%0.0001 Previous surgery16%33% Unknown22%48% IVDA56%6% WRITE STUDY Data on file

7. Final results from 7163 naive, pts enrolled in the PROPHESYS study  To investigate the predictive value of virological responses by week 2, 4 and 12 on SVR.  Patients infected with HCV genotype 2 had the highest rates of on-treatment virological responses and SVR rates among all groups (71% vs 42% in genotype 1)  The highest relapse rates occurred among genotype 1 patients and the lowest relapse rates in genotype 2 patients (27% vs 11% in genotype 1) Marcellin p et al AASLD 2011

8. PROPHESYS STUDY: Virological response over time in HCV 2 and 3 patients wk4 wk 12 EOT SVR 92 91 HCV 3 Marcellin P et al AASLD 2011

9. SVR rates by RVR in HCV-2 pts enrolled in studies on short or standard tx duration No of pts RVR (%) SVR in 12/16 weeks (%) Relapse (%) SVR in 24 weeks (%) Relapse (%) Yu150 8694 (45/50)6 (3/50)95 (95/100)3 (3/100) Shiffman Diago, 455/728 6981 (196/243)17 (39/233)92 (194/212)5 (10/204) vonWagner39 9795 (18/19)0.5 (1/19)95 (18/19)0.5 (1/19) Mecenate116 6880 (32/40)3 (1/34)79 (31/39)0 Dalgard85 7193 (27/29)7 (2/29)97 (30/31)3 (1/31) Mangia213 6487 (89/102)3 (3/98)76 (40/53)3 (1/32)

10. SVR rates by RVR in HCV-3 pts enrolled in studies on short or standard tx duration No of pts RVR (%) SVR in 12/16 weeks (%) Relapse (%) SVR in 24 weeks (%) Relapse (%) Shiffman Diago, 408/728 5684 (236/215)14 (29/206)90 (173/193)7 (13/180) vonWagner113 9176 (39/51)16(8/52)75 (39/52)4 (2/51) Mecenate94 6887 (28/32)3 (1/29)69 (22/32)8 (2/24) Dalgard119 7084 (93/110)15 (17/110)92 (106/115)8 (9/115) Mangia70 5977 (24/31)14 (4/928)100 (10/10)0

11. Rates of non RVR and SVR in pts with HCV- 2 and HCV-3 who received 24 wks of tx No of HCV-2 pts Non RVR (%) SVR after 24 wks in non RVR No of HCV-3 pts Non RVR (%) SVR after 24 wks in non RVR Yu150 14 77 (10/13)NA Shiffman728 43 53 (58/109)72713 39 (58/150) Mangia213 35 78 (45/58)704141 (9/22) Mecenate116 32 60 (22/37)943260 (18/30) Dalgard85 2975 (15/20)3433156 (54/96)

12. SVR Non-SVR TTTCCC p = 1.06 x 10 –25 n=102n=433n=336 TTTCCC n=70n=91n=30 TTTCCC n=14n=35n=26 TTTCCC n=186n=559n=392 p = 2.06 x 10 –3 p = 4.39 x 10 –3 p = 1.37 x 10 –28 CaucasianAfrican American HispanicCombined SVR (%) Ge D, et al. Nature 2009; 461: 399–401 rs 129760 predicts SVR -chromosome 19 -3kb upstream of IL28B -P=1.37 x10 -28 across all population groups SNP near IL28B predicts SVR with PR

13. Completed n=120 Completed n=74 Drop out n=2 Drop out n=3 Drop out n=1 Drop out n=4 HCV-RNA -ve Treated for 12 weeks n=122 HCV-RNA +ve Treated for 24 weeks n=78 Variable-12/24 (VD) PegIFN + RBV for 12 or 24 weeks n=200 Standard-24 (SD) PegIFN + ribavirin for 24 weeks n=68 Original study protocol n=268* Week 4 Week 12 Week 24 * 13 patients did not provide informed consent; genotyping failed in 2 Week 0 Completed n=64 Mangia EASL 2010

14. IL28B-type is associated with increased SVR in non-RVR patients treated with 24 weeks therapy patients treated with 24 weeks therapy

15. Mangia et al. HCV-2 211* SVR 151 (72%) SVR in RVR 108/130 (83%) SVR in noRVR 43/81 (53%) CC79 (37%)60 (76%)39/47 (83%)21/32 (66%) CT101 (48%)72 (71%)57/67 (85%)15/34 (44%) TT31 (15%)19 (61%)12/16 (75%)7/15 (47%) Sarrazin et al HCV-2 77^ SVR^ 51/58 (88%) SVR^in RVR SVR^noRVR CC40 (52%) 51%21/22 (95%)1/4 (25%) CT29 (38%) NA 0 TT8 (10%) NA 0 ^ p=0.09 SVR vs NR (follow up information were not for available in all patients) *in 4 patients IL28B was not determinable

16. IL 28B: clinical implications in G2 and G3 G2 G3 RVR (+) RVR (-) No role for IL28B 24 wks If IL28B CC If unfavourable IL28B 48 wks? DAA?

17. IL28B with the new drugs SILEN C-1 BMS 790052 +Peg-IFN

19.  Design: Phase IIa multicentre, partially blinded, randomised, stratified for genotype, multiple-dose trial in France, Italy, Sweden and UK Study design TVR + Peg-IFN + RBV (triple therapy) (T/PR) Peg-IFN + RBV 2 weeks Screening Follow up for  24 weeks after EOT 24 weeks (T mono arm) 22 weeks (T/PR and PR arms) TVR (T mono) TVR 750 mg q8h; Peg-IFN alfa-2a 180  g/week; RBV 800mg/day EOT = end of treatment; PBO = placebo PBO + Peg-IFN + RBV (PR)

20. Median HCV RNA decline from baseline – G2 Median change in log10 HCV RNA T mono (n=9) PR (n=9) T/PR (n=5) Time (Days) –4.83 –5.51 –3.66

21. Study Design PROTON 125 treatment-naïve patients with HCV GT1 Planned 12 Week Interim analysis: Nelson, et al. EASL LB poster #1372 Week 0 12 48 72 24 PSI-7977 200 mg QD Peg-IFN + RBV PSI-7977 200 mg QD Peg-IFN + RBV PSI-7977 400 mg QD Peg-IFN + RBV PSI-7977 400 mg QD Peg-IFN + RBV SVR Follow-Up Peg-IFN + RBV Non-RVR Peg-IFN + RBV STOP Non-RVR Peg-IFN + RBV STOP N=50 N=25 HCV GT1 25 treatment-naïve patients with HCV GT2/3 PSI-7977 400 mg QD Peg-IFN + RBV PSI-7977 400 mg QD Peg-IFN + RBV N=25 Week 0 12 HCV GT2/GT3 SVR24 SVR12

22. Week 2 Week 4 RVR Week 12 cEVR/EOT SVR12 n (evaluable) 24 HCV RNA < LOD* 2124 % Response 88%100% Lost to follow-up 1111 % Response (ITT) 84%96% *Roche COBAS TaqMan, LOD 15 IU/mL PROTON HCV GT2/GT3 Antiviral Responses

23. PSI-7977 Electron study-GT 1/2/3

24. Electron study: concordance SVR12 /SVR 24

25. DEBIO 025 or Alispovir Rice CM 2011

26. Alisporivir 600 mg BID + RBV Alisporivir 600 mg BID + PegIFN Week Alisporivir 800 mg QD + RBV* 24 ALV1000 n=83 ALV-P n=39 1 Alisporivir 600 mg BID Alisporivir 600 mg BID + RBV ALV800R n=94 ALV600R n=84 Alisporivir 600 mg QD + RBV* 26 Alisporivir in GT-2/3: the VITAL study Pawlotsky JM, et al. AASLD 2011. Abstract LB-11 PegIFN/RBV PR n=40 phase IIb trial of alisporivir in treatment-naïve HCV GT-2 or GT-3 patients Alisporivir 1000 mg QD* Alisporivir 600 mg QD + PegIFN* *Patients with HCV RNA ≥25 IU/mL at Week 4 received alisporivir 600 mg QD + PegIFN/RBV from Week 6 until Week 24

27. 27 Pawlotsky JM, et al. AASLD 2011. Abstract LB-11 Alisporivir in GT-2/3: the VITAL study

28. Conclusions HCV 2 infected represent up to 27% of chronic pts PegIFN/RBV ensure rates of SVR up to 90% even after 12-16 weeks of treatment In HCV 2 pts, IL28B has an impact lower than in HCV 1 IFN free regimen might became a valuable alternative to further reduce the Tx duration

29. Thank you