2. Predictors of treatment response, baseline and on-treatment A case study of telaprevir therapy Alex Thompson

3. Key learning objectives Identify the key predictors of treatment response for HCV genotype 1: – peg-IFN + RBV IL28B genotype, fibrosis stage, baseline viral load On-treatment response (RGT) – DAA – telaprevir IL28B genotype, fibrosis stage, HCV 1a vs 1b Past treatment response Importance of on-treatment response – eRVR (RGT) – Stopping rules

4. Mrs CW 55-year-old professional woman Experimental IDU in early 20s Moderate-heavy alcohol intake 25-50 years – 40-60 g alcohol/day – Abstinent since diagnosis of HCV 3 years prior No symptoms of HCV or CLD

5. Mrs CW Obese (BMI 37) Hyperlipidaemia Glucose intolerance Medication – Atorvastatin – Fish oil tablets

6. Mrs CW What results do you want to know?

7. Mrs CW Investigation results: – FBE – platelets 130 – LFTs – albumin 36, ALT 150, BR 6 – HCV – 1a – HCV viral load 900,000 IU/mL – IL28B genotype TT – Fasting glucose 6.2, fasting lipids TC 5.6, LDL 3.0 – US – echogenic liver c/w fatty infiltration, spleen at upper limit normal

8. Mrs CW Fibroscan – not possible (body habitus) Liver biopsy – cirrhotic

9. Mrs CW What is the likelihood that she will be cured: – peg-IFN + RBV? – DAA therapy?

10. Peg-IFN + RBV

11. peg-IFN + RBV: SVR rates 0 20 40 60 80 100 8-12% SVR (%) 15-20% 38-43% 25-30% 50-60% Standard IFN (6 mths) [1] Standard IFN (12-18 mths) [2,3] IFN / RBV (6-12 mths) [3,4] peg-IFN monotherapy (6-12 mths) [5,6] peg-IFN / RBV (6-12 mths) [6,7] 1. Carithers RL Jr., et al. Hepatology. 1997;26:83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 1991 200119951998

12. peg-IFN alfa-2b 1.0 µg/kg/wk + RBV 800-1400 mg/day peg-IFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day ITT analysis (n=3070) IDEAL Study: peg-IFN alfa-2a vs alfa-2b in treatment-naive HCV genotype 1 patients 40% 38% 41% 0 20 40 peg-IFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day SVR (%) 60 80 100 McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

13. 0 20 40 60 80 100 Response rate (%) 33 SVR n=1171 27 69 TT CT CC peg-IFN and RBV: IL28B-type and fibrosis stage predict for SVR in HCV genotype 1 Thompson, Gastro, 2010 0 20 40 60 80 100 34 30 72 TT CT CC 0 20 40 60 80 100 22 11 41 TT CT CC SVR n=133 SVR n=988 F0-2F3-4 HCV-1

14. Marcellin, AASLD, 2007 Fried, EASL, 2008 SVR <5% SVR 29% SVR 88% SVR 68% 10 6 10 5 10 4 10 3 10 2 10 4 812 2024 48 wks Likelihood of SVR HCV RNA (IU/mL) // 0 RVRcEVR pEVR 2 log 10 IU/mL decline Undetectable < 50 IU/mL 16 % 42 % 22 % 20 % NR peg-IFN + RBV: On-treatment virological response predicts SVR in HCV genotype 1

15. Telaprevir therapy

16. ADVANCE: Telaprevir + peg-IFN/RBV in HCV-1 treatment-naive patients Treatment-naive patients with genotype 1 HCV (n=1088) 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, peg-IFN 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. N Engl J Med. 2011;364:2405-2416. Wk 24 PR* eRVR † : PR* PR* Follow-up

17. p<0.001 SVR (%) 0 20 40 60 80 100 PRT12 PR 75 271/ 363 44 158/ 361 n/ N = 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Dusheiko GM, et al. EASL 2011. Abstract 1788. Pooled analysis from ADVANCE and ILLUMINATE [2] ADVANCE [1] SVR (%) 0 20 40 60 80 100 PRT12 PR n/ N = Nonblack Black 75 599/ 804 61 60/ 99 45 151/ 333 25 7/ 28 Telaprevir triple therapy: SVR rates in treatment-naïve genotype 1 patients Delta = 33%

18. T12/PR 683/903 PR 48 166/361 n/N = 74–79* Telaprevir EU SmPC *p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE. SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Telaprevir triple therapy: SVR rates in treatment-naïve genotype 1 patients*

19. Predicting response in treatment-naïve patients: 1.Baseline: – Fibrosis stage – IL28B genotype – Other - Genotype 1a vs 1b, HCV viral load, etc. 2.On-treatment: – Extended RVR (eRVR) and response-guided therapy (RGT) – Stopping rules Telaprevir

20. *

21. SVR (%) PR 48 140/288 n/N= Telaprevir EU SmPC T12 PR 237/290 PR 48 18/52 T12 PR 33/52 F0 – F2F3 SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used PR 48 8/21 T12 PR 15/21 Cirrhosis SVR by advanced fibrosis or cirrhosis in patients receiving TVR + peg-IFN/RBV

22. Direct antiviral therapy & IL28B ADVANCE (telaprevir, treatment-naïve) n=454/1088 (42%) Jacobson, EASL, 2011 22 68 5032 76 4526 80 55

23. Extended RVR (eRVR) = undetectable HCV RNA at Weeks 4 and 12 Patients with undetectable HCV RNA (%) Week 4 (RVR)Weeks 4 and 12 (eRVR) Patients eligible to receive 24 weeks of treatment in total PR 48 34/361 T12 PR 635/903 T12 PR 565/903 PR 48 29/361 n/N= Adapted from Sherman KE, et al. CROI 2011. Abstract 957 58 -65% 66-72%

24. Telaprevir: SVR rates by eRVR status SVR (%) PR 48 27/29 n/N= eRVR+ eRVR– T12 PR 195/212 PR 48 139/332 T12 PR 90/151 24-week regimen 48-week regimen Telaprevir EU SmPC SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

25. IL28B CC genotype predicts for short duration therapy ADVANCE – Telaprevir arms, n=293 Jacobson, EASL, 2011 HCV RNA undetectable (%)

26. Telaprevir: Duration of therapy for treatment-naive patients After 12 wks, telaprevir should be discontinued and peg-IFN/RBV continued – Cirrhotic patients with undetectable HCV RNA at Wks 4 and 12 may nevertheless benefit from additional 36 wks of peg-IFN/RBV (48 wks total) rather than response-guided therapy Response-Guided Therapy HCV RNATriple Therapy: TVR + peg-IFN/RBV Dual Therapy: peg-IFN/RBV Total Treatment Duration Undetectable at Wks 4 and 12First 12 wksAdditional 12 wks24 wks Detectable (but ≤1000 IU/mL) at Wks 4 and/or 12 First 12 wksAdditional 36 wks48 wks Stopping Rules Time PointCriteriaAction Wk 4 or 12HCV RNA >1000 IU/mLDiscontinue all therapy Wk 24HCV RNA detectableDiscontinue peg-IFN/RBV AnyDiscontinuation of peg-IFN/RBV for any reasonDiscontinue TVR Telaprevir [package insert]. 2011.

27. Mrs CW Key issues: – Treatment naïve – Cirrhotic – Poor response IL28B genotype – HCV-1a – High VL – Obese/metabolic syndrome

28. Mrs CW OPTIMIZE study: Telaprevir BD Well tolerated Week 4 HCV RNA = detected <1000

29. Retrospective analysis of TVR Ph III trials underscores validity of TVR futility rules No pt with HCV RNA >1000 IU/mL at Wk 4 (n=25) or Wk 12 (n=12) had SVR Viral kinetics analysis of pts with HCV RNA >1000 IU/mL at Wk 4 – 23 of 25 reached HCV RNA nadir before Wk 4 – In most pts, HCV RNA already increasing from nadir by Wk 4 Emergence of highly TVR-resistant variants in majority of pts with HCV RNA >1000 IU/mL at Wk 4 Jacobson I, et al. EASL 2012. Abstract 55. HCV NS3/4A variant Level of TVR resistance Tx-naive pts with HCV RNA >1000 IU/mL at Wk 4, n (n=14) Tx-exp’d pts with HCV RNA >1000 IU/mL at Wk 4, n (n=11) V36M + R155KHigh 12* 8 A156S/T/VHigh 1 0 R155KLow 0 2 Wild typeNone 1 1 *1 patient had R155K present at baseline. Tx Experienced (n = 11)Tx Naive (n = 14) Wks on treatment 024681012 10 10 2 10 3 10 4 10 5 10 6 10 7 10 8 024681012 10 10 2 10 3 10 4 10 5 10 6 10 7 10 8 HCV RNA, IU/mL Wks on treatment

30. Mrs CW OPTIMIZE study: Telaprevir BD Week 12 HCV RNA = 33 – Stopping rule for the study Continued on peg-IFN / RBV off-study Week 16 HCV RNA = 62,000 Treatment stopped

31. Key issues: Telaprevir – Predicting response in treatment-naïve HCV-1 patients: 1.Baseline predictors of SVR: – Fibrosis stage – IL28B genotype – HCV-1a vs 1b 2.On-treatment response: – eRVR – Week 4, week 12 stopping rules

32. PR* REALIZE: Telaprevir + peg-IFN/RBV in HCV-1 treatment-experienced patients Treatment- experienced patients with genotype 1 HCV (n=663) Wk 12 TVR + PR* (n=264) TVR + PR* (n=266) PR* (n=132) Wk 72 Wk 48 Wk 4 Follow-up *TVR 750 mg q8h, peg-IFN 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. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428 PR* Follow-up Wk 16

33. Telaprevir triple therapy: SVR in prior relapsers, partial responders, null responders PR 48 4/27 T12/ PR 48 30/49 SVR (%) Prior relapsersPrior partial responders LI T12/ PR 48 27/48 n/N= PR 48 2/37 T12/ PR 48 22/72 LI T12/ PR 48 25/75 PR 48 15/68 T12/ PR 48 122/145 LI T12/ PR 48 124/141 Prior null responders * * * * ** Telaprevir EU SmPC *p<0.001 vs PR 48. SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

34. IL28B genotyping is less useful if IFN-experienced Relapsers Partial responders Null responders

35. 40 52 7 69 75 29 0 20 40 60 80 100 BOC RGTBOC/PR 48PR 48 Previous partial response Previous relapse n/N = 23/57 72/105 30/58 77/103 2/29 15/51 SVR (%) Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Boceprevir triple therapy: SVR rates by previous response RESPOND-2PROVIDE Bronowicki J, et al. EASL 2012. Abstract 11. e

36. Boceprevir triple therapy: SVR rates in treatment-naïve genotype 1 patients p<0.001 Non-black Patients p=0.04 p=0.004 Black Patients 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 55 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 40 67 68 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 23 42 53 n/ N= Poordad F, et al. N Engl J Med. 2011;364:1195-1206. SPRINT-2 Delta = 27%

37. Proposed clinical decision point Poor IFN responders might defer Tx awaiting DAA combinations BUT : Increases complexity of treatment protocol Need for rapid turn-around of viral load testing ≥ 1 log reduction in HCV RNA stratifies for: 4 week lead-in defines IFN responsiveness (boceprevir experience) SPRINT-2, Poordad, NEJM, 2011

38. REALIZE: Lead-in vs previous response category as predictors of response to TVR Among treatment-experienced patients, previous response categorisation is a stronger predictor of SVR with TVR-based therapy than on-treatment response to lead-in – Deciding whether to treat based on lead-in response would exclude many patients with a good chance of SVR However, previous null responders had a >3-fold lower likelihood of achieving SVR with TVR-based therapy if HCV RNA decreased by <1 log 10 vs ≥1 log 10 after 4-wk lead-in Foster GR, et al. EASL 2011. Abstract 6. Relapsers Partial non-responders Null responders 100 0 60 SVR (%) 80 40 8/ 13 20 62 < 1 log≥ 1 log Decline in HCV RNA at Wk 4 10/ 18 56 6/ 41 15 106/ 113 94 16/ 27 59 15/ 28 54 n/N = ?

39. REALIZE (telaprevir): SVR rates by IL28B genotype and prior response to peg-IFN/RBV Pol S, et al. J Hepatol 2011;54(Suppl. 1):S6 Prior relapsers SVR (%) Prior partial responders Prior null responders Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) CCCTTTCCCTTTCCCTTT n/N= n/a 29/344/126/30100/1173/101/55/82/1033/570/510/144/101/1827/921/1510/3251/58