1. AASLD 2010 HCV Feedback October 29 - November 2, 2010 Boston, Massachusetts Dr Allister J Grant Consultant Hepatologist Leicester Liver Unit

2. 1.Boceprevir, a potent inhibitor of HCV NS3 protease 2.Telaprevir, a potent inhibitor of HCV NS3/4A protease 3.Both being tested in combination with standard-of- care peginterferon alfa-2/ ribavirin in phase III studies in chronic HCV infection Trials reported at AASLD 2010 1.Boceprevir SPRINT-2: naive GT1 patients RESPOND-2: nonresponder GT1 patients 2.Telaprevir ADVANCE: naive GT1 patients ILLUMINATE: response- guided therapy in naive GT1 patients Boceprevir and Telaprevir

3. Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 316, 52) PR* (n = 311 nonblack, 52 black) Wk 72 Wk 48 Follow-up Wk 28 Follow-up Wk 4 BOC + PR* (n = 316 nonblack, 52 black) BOC + PR* (n = 311 nonblack, 55 black) PR* (n = 311, 55) PR* *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. † Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Poordad F, et al. AASLD 2010. Abstract LB-4. Follow-up RVR † No RVR  Phase III, Randomized, placebo-controlled trial SPRINT-2: Boceprevir + PegIFN/RBV in G1 Tx-Naive Patients PR* (n = 311, 52 )

4. 0 20 40 60 80 100 Patients (%) SVR Relapse 4-wk PR + 44 weeks BOC + PR4-wk PR + response-guided BOC + PR48-wk PR 67 68 40 8 23 9 0 20 40 60 80 100 Patients (%) SVRRelapse 42 53 23 17 14 12 Nonblack Patients Black Patients P <.0001 P =.044 P =.004 Poordad F, et al. AASLD 2010. Abstract LB-4. n =211 213125 21 183722 2912 362 SPRINT-2: Response Rates According to Race

5. SPRINT-2: Response Rates >1 log drop in VL at wk 4: – 82% SVR for both B/PR arms <1log drop in VL at wk 4: – 28% SVR in RGT (response guided therapy) – 38% SVR in 44BOC/PR PCR neg at week 4 and 8 – 97% SVR in RGT (47% of patients) – 98% SVR in 44BOC/PR

6. RESPOND-2: Boceprevir in G1 Prior Non-responders to PegIFN/RBV Phase III, Randomised PR* (n = 80) PR* (n = 161) BOC + PR* PR* (n = 162) BOC + PR* If detectable at Wk 8 PR* Bacon BR, et al. AASLD 2010. Abstract ♯ 216. Treatment- experienced patients with GT1 HCV (N = 403) Wk 48 Wk 8 Wk 36 Follow-up † *BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. † Follow-up for 24 wks after completion of therapy. Wk 4

7. 0 20 40 60 80 100 Overall SVR (%) 4-wk PR + 44-wk BOC + PR (n = 161) 59* Previous Nonresponders Previous Relapsers 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162) 66 21 40 52 7 75 29 69 P <.0001 vs control (both arms) Bacon BR, et al. AASLD 2010. Abstract 216. 95/ 162 107/ 161 17/ 80 23/ 57 30/ 58 2/29 72/ 105 77/ 103 15/ 51 RESPOND-2: SVR Rates According to Treatment Arm and Prior Response

8. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. Treatment- naive patients infected with genotype 1 HCV (N = 250) 12-Wk Arm TVR* + PegIFN/RBV † (n = 17) PegIFN/RBV* Wk 12 48-Wk Control Arm PegIFN/RBV † + Placebo (n = 75) 48-Wk Control Arm PegIFN/RBV † + Placebo (n = 75) 24-Wk Arm TVR* + PegIFN/RBV † (n = 79) 48-Wk Arm TVR* + PegIFN/RBV † (n = 79) PegIFN/RBV* Wk 24 Wk 48 24-wk follow-up *1250 mg loading dose of TVR administered on Day 1, then 750 mg 3 times daily. † PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day. PROVE 1 : Combination of Telaprevir with PegIFN/Ribavirin significantly increases SVR in treatment-naïve patients with HCV Genotype 1

9. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 0 20 40 60 80 100 Patients (%) 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 12-wk TVR + pegIFN/RBV (n = 17) Control (n = 75) SVRRelapse 35 61 † 41 67 ‡ 33 2 23 6 N/A, not applicable. *P <.001 vs control. † P =.02 vs control. ‡ P =.002 vs control. PROVE 1: Results

10. Frequency of undetectable HCV RNA levels during and after treatment WeekT12/PR24 N=79 T12/PR48 N=79 T12/PR12 N=17 PR48 N=75 464(81%) 10(59%)8(11%) 1254(68%)63(80%)12(71%)34(45%) 2445(57%)56(71%)NA43(57%) 48NA51(65%)NA35(47%) SVR48(61%)53(67%)6(35%)31(41%) 12% 14% McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

11. T12/PR24 vs T12/PR48 T12/PR24T12/PR48 RVR81% SVR61%67% Relapse2%6% DC 2° to A/E25.3%13.9% Dropouts47%32% McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

12. PROVE 1: Conclusions 1.Coadministration of a 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV significantly increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone 2.Coadministration of TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV 3.TVR coadministration increased rate of treatment discontinuation due to adverse effects, predominantly rash McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

13. Prove 3 McHutchison JG, et al. AASLD 2009. Abstract 66, NEJM 2010. OutcomeControl Arm (n = 114) 12-Wk TVR + 24-Wk PegIFN/RBV (n = 115) 24-Wk TVR + 48-Wk PegIFN/RBV (n = 113) 24-Wk TVR + PegIFN (n = 111) SVR, %1451*53*24 †  Previous nonresponders, % (n/N) 9 (6/68)39* (26/66)38* (24/64)11 ‡ (7/62)  Previous relapsers, % (n/N) 20 (8/41)69* (29/42)76* (31/41)42 § (16/38)  Cirrhotics %8534518 *P <.001 vs control. † P =.024 vs control. ‡ P =.297 vs control. § P =.029 vs control. 24 vs 48wks of T/PR in patients with G1 previously treated with PEG IFN/ RBV- Week 4 non-response - <1log decline in control arm or detectable HCV in TPR arms

14. ADVANCE: Telaprevir + PegIFN/RBV in G1 Tx-Naive Patients Wk 12 TVR + PR* (n = 364) TVR + PR* (n = 363) PR* (n = 361) eRVR † : PR* Wk 72 Wk 48 Wk 8 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. † eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. AASLD 2010. Abstract 211. Wk 24 PR* eRVR † : PR* PR* Follow-up  Phase III, Randomized, placebo-controlled trial Treatment-naive patients with genotype1 HCV (N = 1088)

15. ADVANCE: 1088 Treatment naïve G1 patients randomised: TPV/PEG/RBV x8 weeks then PEG /RBV x16 weeks (T8/PR24) TPV/PEG/RBV x12 weeks then PEG /RBV x12 weeks (T12/PR24) PEG/RBV x48 weeks (PR48) RESULTS: T8/PR24 N=364 T12/PR24 N=363 PR48 N=361 RVR (%)67689 eRVR (%)57588 SVR (%)697544 eRVR-  SVR838997 Completion %71.473.856 PR Viral breakthrough 10.25NA Jacobson I AASLD ♯ 211 Kiefer T AASLD LB-11

16. ILLUMINATE: Response-Guided Telaprevir + PegIFN/RBV in G1 Naive Pts Treatment- naive patients with GT1 HCV (N = 540) PR* (n = 162) PR* (n = 160) Wk 72Wk 48Wk 24 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. † eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Sherman KE, et al. AASLD 2010. Abstract LB-2. Follow-up  Phase III Open-label, randomized trial, ITT analysis Wk 20 eRVR † No eRVR † PR* (n = 218) TVR + PR* Wk 12 PR*

17. 0 20 40 60 80 100 24-wk therapy SVR (%) 92 48-wk therapy 88 Overall 72 Patients With eRVR n/N =388/540149/162 140/160 Sherman KE, et al. AASLD 2010. Abstract LB-2. ILLUMINATE: Overall SVR Rates

18. ILLUMINATE: Adverse Events – Anaemia <8.5 9% in TPV 2% in PR 0.6% DC – Fatigue (1.1% DC) – Rash Eczematous rash in 37% 7% severe rash – Pruritis – Nausea Overall discontinuation rate 17% In first 12 weeks there was: – 7% DC of all drugs – 12% DC of Telaprevir

19. Interferon Free Therapy? BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in G1 Null Responders Lok A, et al. AASLD 2010. Abstract LB-8. Prior null responders with GT1 HCV (N = 21) BMS-790052 60 mg QD + BMS-650032 600 mg BID (n = 11) Wk 72 Wk 24 Follow-up BMS-790052 60 mg QD + BMS-650032 600 mg BID + PR* (n = 10)  Open-label, randomized, placebo-controlled phase IIa trial  BMS-790052: NS5A polymerase inhibitor  BMS-650032: NS3 protease inhibitor Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.

20. Wk 12 Interim Analysis 64 36 46 60 90 0 20 40 60 80 100 RVReRVRcEVR BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR Patients (%) 7/116/10 4/115/119/10  All viral breakthroughs occurred in patients with GT1a Lok A, et al. AASLD 2010. Abstract LB-8.

21. Other Protease/Polymerase Inhibitors TMC435- NS3/4a Protease inhibitor (PILLAR Trial) – Phase IIa, G1 Naive – Once Daily – 12-24 weeks Rx +PR48 – SVR 91%-98% (4 vs12 wks ) Daneprovir – RG7227 phase II, in G1 naive patients (ATLAS trial) – 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs 43% with SOC Vaniprevir- NS3/4a Protease Inhibitor – MK-7009 phase IIa study G1 naive patients without cirrhosis – Significantly higher when combined with pegIFN/RBV vs SOC RVR: 67% to 84% vs 5% Fried M, et al. AASLD 2010. Abstract LB-5. Terrault N, et al. AASLD 2010. Abstract 32. Manns MP, et al. AASLD 2010. Abstract 82

22. HCV Pharmacogenetics GWAS used patients from IDEAL and Muir Studies 1137 samples on patients with SVR SNP’s rs12979860 on Chr 19 strongly associated with SVR & localised to IL28β SVR % Thomas DL, et al. Nature. 2009;461:798-801.

23. Regional Distribution of IL28B rs12979860 CC Genotype

24.  IL28β polymorphisms associated with – Higher SVR rates [1] – Higher RVR rates [2] – Higher HCV RNA [3] – Higher LDL levels [4] – Higher baseline ALT levels [5] – Higher rate of spontaneous viral clearance [6] 1. Ge D, et al. Nature. 2009;461:399-401. 2. Mangia A, et al. AASLD 2010. Abstract 897. 3. Liu L, et al. AASLD 2010. Abstract 231. 4. Saito H, et al. AASLD 2010. Abstract 732. 5. Thompson AJ, et al. AASLD 2010. Abstract 1893. 6. Thomas DL, et al. Nature. 2009;461:798-801. IL28β Associations in Patients With Hepatitis C

25. And if time

26. ♯ 214:Maintenance PEG IFN to prevent HCC Extended FU from HALT-C trial 1084 patients 6.1-8.7yr FU 88 HCC (20 clinical HCC) No difference between Rx and Control at 3/5/7yr Subgroup analysis – Cirrhotics who had PEG for >2 years- marginal benefit A Lok et al AASLD 2010, Abstract 214

27. EXTEND Trial: Long Term FU of PROVE 1-3 patients 3 yr FU of T/PR treated patients 123 patients who had SVR’s from previous studies 122/123 had durable SVR (99%) 79 patients without SVR analysed for resistance and after 22 mo 89% reverted to wild type S Zeuzem et al AASLD 2010, Abstract 227

28. ♯ 213: Effect of SVR on all cause mortality Dept of Veterans Affairs Data Registry 23000 patients 16800 with post Rx RNA, SVR rate 44% – 52% smokers, 20% DM, 15% COPD, 12% CAD, 26% alcohol, 36% depression – 1535 died (median 3.7yrs) Time Mortality G1,2,3 with SVR G1,2 No SVR G3 No SVR