1. Response Guided Vs.Response Unguided Therapy K.Rajender Reddy M.D Professor of Medicine University of Pennsylvania Philadelphia, USA

2. Factors in Complexity of HCV Therapy Lead In No Lead In Age/Gender IL28B Relapser Partial Responder Null Responder Treatment Naïve Obesity Race/ethnicity Viral load/Genotype

3. Protease Inhibitor Based HCV Therapy: Easy to Treat and Difficult to Treat Genotype 1 Patient Populations Easy to Treat Low viral load Women Younger age Absence of fibrosis IL 28 B CC Interferon sensitive Relapsers Difficult to Treat High viral load Obesity/Metabolic syndrome Blacks IL 28 B-C/T, T/T Cirrhosis Older population Interferon insensitive Partial and Null Responders Response Guided Therapy Response Unguided Therapy

4. Protease Inhibitor Trials: Summary Treatment Naïve –Telaprevir (TPV) ADVANCE -- RGT ILLUMINATE –RGT and RUGT –Boceprevir (BOC) SPRINT-2 –RGT + RUGT Treatment Experienced –Telaprevir (TPV) REALIZE –RUGT –Boceprevir (BOC) RESPOND-2 –RGT + RUGT

5. Limitations and Unique Aspects of the Trials In both TPV and BOC studies, small number of Patients with cirrhosis Older population High BMI patients ( Post-Hoc Analyses) IL-28B –Boceprevir – limited data –Telaprevir – limited data Blacks –Boceprevir Prospective study –Telaprevir Post-hoc analysis Prior Treatment Experienced –Boceprevir – RGT + RUGT –Telaprevir – RUGT

6. ADVANCE: Overall SVR and Relapse Rates According to Treatment Arm Jacobson IM et al. N Engl J Med 2011;364:2405-2416. % of Patients T12PR T8PR PR 271/363 250/364 168/361 17/264 18/247 51/189

7. ADVANCE: SVR for T12PR in Selected Subgroups Jacobson IM et al. N Engl J Med 2011;364:2405-2416. SVR (%) 112/ 149 244/ 325 159/ 214 16/ 26 Male  45 yrs White Female >45 to  65 yrs Black 118/ 142 150/ 214

8. ADVANCE: SVR for T12PR in Selected Subgroups Jacobson IM et al. N Engl J Med 2011;364:2405-2416. 245/ 328 64/ 82 26/ 35 207/ 281 HispanicHCV Subtype 1aHCV RNA <800,000 Non-HispanicHCV Subtype 1b HCV RNA  800,000 152/ 213 118/ 149 SVR (%)

9. ADVANCE: SVR for T12PR in Selected Subgroups Jacobson IM et al. N Engl J Med 2011;364:2405-2416. SVR % 117/ 156 55/ 77 109/ 134 87/ 129 No/Minimal FibrosisBMI <25 (Normal) Portal Fibrosis BMI  25 to <30 (Overweight) Bridging fibrosis BMI  30 (Obese) Cirrhosis 32/ 52 129/ 155 13/ 21

10. Cirrhosis

11. ILLUMINATE(TPV): SVR in Cirrhosis and Blacks in those with eRVR ( T12/PR24 Vs.T12/PR48) SVR % T12|PR24(RGTT12|PR24 T12|PR48(RUGT)T12|PR48 RUGT 12/1811/1215/1716/17 FDA analysis and Sherman KE, et al. N Engl J Med 2011;365:1014-24 10

12. SPRINT-2: SVR and Relapse Rate by Fibrosis Score SPRINT-2 and RESPOND-2: BOC + PegIFN/RBV in HCV GT 1 with Advanced Fibrosis/Cirrhosis N=328N=319N=24 N=34N=42N=158N=233N=231N=12N=17N=25 N=313 Bruno S, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 7.

13. RESPOND-2: SVR by Cirrhotics (F4) vs. Non- Cirrhotics (F0/1/2/3) According to Treatment Arm % of Patients PR 48 RGT BOC/PR48 0/106/1717/2216/6685/13285/128 RUGT Bacon BR et al. N Engl J Med 2011;364:1207-1217.

14. Treatment Naïve-Blacks

15. SPRINT-2: SVR in Primary Patient Cohorts According to Treatment Arm Poordad F et al. N Engl J Med 2011:364:1195-1206. PR48 RGT BOC/PR48 p<0.001 p=0.004 p=0.04 All Patients (Both Cohorts) Nonblack CohortBlack Cohort 137/ 363 233/ 368 242/ 366 137/ 363 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 53 SVR (%) RUGT

16. Prior Treatment Experienced

17. RESPOND-2: SVR and Relapse Rates for All Subjects According to Treatment Arm % of Patients PR48 RGT BOC/PR48 n=80n=162n=161n=25n=111n=121 Bacon BR et al. N Engl J Med 2011;364:1207-1217.

18. RESPOND-2: SVR by Response to Previous Peg-IFN/RBV Therapy According to Treatment Arm* PR 48 RGT BOC/PR48 2/29 23/5730/58 16/5173/10577/103 SVR (%) RUGT Bacon BR et al. N Engl J Med 2011;364:1207-1217.

19. RESPOND-2: SVR According to Viral Load Bacon BR et al. N Engl J Med 2011;364:1207-1217. PR48 RGT BOC/PR48 12/1511/6583/14791/14116/206/15  SVR (%) RGT vs RUGT

20. Interferon Response

21. SPRINT-2 and RESPOND-2: Evaluation of Predictive Value of PegIFN/RBV 4-week Lead-in Therapy Vierling JM, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011: Abst. 481. Relationships Between Week 4 Lead-in and SVR Poorly responsive to interferon <1.0 log 10 viral load decline at treatment Week 4 Responsive to interferon ≥1.0 log 10 viral load decline at treatment Week 4 133/ 203/200/ 3/8327/9736/950/1215/4615/44 260 252 25417/6780/11090/114

22. SVR for Relapsers ( eRVR and SVR;T12PR 48 and T12PR24) SVR % eRVR SVR in eRVR REALIZEEARLIER PHASE STUDIES (106 and 107) 218/286208/21852/67 49/52

23. IL 28 B

24. SPRINT-2 ( Treatment Naïve): SVR by IL28B Polymorphism % SVR 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 * ~90% eligible for short duration therapy * Poordad F, et al. EASL 2011, Abst.. RGT vs RUGT

25. RESPOND-2( Treatment Experienced): SVR by IL28B Polymorphism 6 13 22 28 17 22 5 29 38 62 48 66 5 10 6 11 13 18 * ~80% eligible for short duration therapy Poordad F, et al. EASL 2011, Abst.. % SVR * RUGT

26. HCV Therapy: Candidates for Response Unguided Therapy Easy to Treat Absence of fibrosis Low viral load Younger age Women IL 28 B CC Interferon sensitive Relapsers Difficult to Treat High viral load Obesity/Metabolic syndrome Blacks IL 28 B-C/T, T/T-Treatment Experienced Cirrhosis Older population Interferon insensitive Null and Partial Responders Response Unguided Therapy