1. Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy ELPA Symposium: COMPASSIONATE USE IN HEPATITIS C What patients populations have the highest unmet needs ?

2. Patients population with the highest unmet need Cirrhosis Patients without response to previous therapy (triple & double) Patients intolerant to Interferon

3. Patients population with the highest unmet need Cirrhosis Patients without response to previous therapy (triple & double) Patients intolerant to Interferon

4. No SVR SVR 100 Patients With Liver Complications (%) 80 60 40 20 0 168024487296120144 Mos 759 124 702 119 634 116 527 108 345 70 207 41 34 12 Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis Bruno S, et al. Hepatology. 2007;45:579-587. Pts at Risk, n

5. Cirrhosis: Efficacy of triple therapy in HCV G1 StudyNaïveRelapsersPartial Responders Null Responders Telaprevir Phase III Studies 1-2 71% (F4) 59% (F3-F4) 84% (F4) 34% (F4) 14% (F4) Boceprevir Phase III Studies 3-5 42%83% (F3-F4) 46% (F3-F4) 1/2 CUPIC Real Life Telaprevir 6 _71% (SVR 12) 29% (SVR12) _ CUPIC Real Life Boceprevir 6 _52% (SVR 12) 31% (SVR 12) _ 1.Marcellin P, et al. J Hepatol 2011; 54 (Suppl 1): S183 2. Pol S, et al. Hepatology 2011;54(Suppl. S1):374A 3. Buti M. AASLD 2012 3. Poordad F, et al. N Engl J Med 2011;364:1195–206 4. Bacon BR, et al. N Engl J Med 2011;364:1207–17 5. Vierling J et al AASLD 2011 6. Hezode C et al EASL 2013 Submitted

6. Safety in cirrhotics: Clinical Trials vs Real World n=530n=323 n=734n=727 n=159n=296 Clinical trials (including cirrhotics) Real world (cirrhotics only) Treatment-naïveTreatment-experienced Telaprevir Boceprevir n=132n=80 n=363n=361 PegIFN/RBV (courtesy F. Poordad)

7. CUPIC: Risk of occurrence of death or severe complications FactorsPlatelet count > 100.000 Platelet Count < 100.000 Albumin > 3.5 g/dL 3.3%4.8% Albumin < 3.5 g/dL 7.1%40.6% Hezode C et al EASL 2013 Submitted

8. Standard of Care (PEG IFN + RBV) in Decompensated Cirrhosis Martinez-Camacho A, Fortune BE, Everson GT. Treating HCV Prior to Liver Transplantation. In Chronic Hepatitis C: Advances in Treatment, Promise for the Future. ML Shiffman (ed). 2012. Springer Science-Business. NY. HCV-RNA Neg AuthorNRxEOTSVR Iacobellis66Peg/RBV49%20% Forns51Peg/RBV29%20% Tekin20Peg/RBV45%30% Annichiarico15Peg/RBV47%20% Everson124IFN/RBV46%24% Forns30IFN/RBV30%20% Thomas20IFN60%20% Amarapukar18IFN/RBV61%38% Crippin15IFN/RBV33%0% TOTALS35944%24%

9. Deaths and AEs in the first 6 month of follow-up according to treatment or not OR 0.7 OR 0.6 OR 0.6 OR 0.9 OR 2.4 2.4 (1.02 – 5.77) OR 2.9 OR 1.2 OR 1.9 Iacobellis A, et al. J Hepatol 2007 Safety and tolerability

10. G1 Cirrhosis awaiting LT DAA in PNC-HCV Triple therapy (PR + TPV or BOC)

11. G1 Cirrhosis awaiting LT DAA in PNC-HCV Triple therapy (PR + TPV or BOC)

12. Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients

13. SOUND-C2: Faldaprevir + BI-207127 ± R in treatment-naїve patients SVR12: cirrhosis vs. no cirrhosis 100 80 60 40 20 0 67 57 52 11/21 124/217 6/9 70 40 33 48/69 1/3 17/43 CirrhosisNo cirrhosisCirrhosis No cirrhosis BI 207127 dosingTIDBIDTID Duration (weeks)16, 28 & 4028 RBV++- The presence of cirrhosis did not significantly influence the achievement of SVR12 in univariate regression analysis (odds ratio 0.84; p=0.66) Soriano V et al. AASLD 2012: http://www.natap.org/2012/AASLD/AASLD_19.htm

14. Ribavirin + Sofosbuvir + PEGIFN Data in 153 cirrhosis Summary of Fusion (68 HCVG2&3 experienced), Fission (100 HCV G2&3 naives), Positron (31 HCV G2/3 IFN intolerant) and Neutrino (54 G1&4-6 naives) Studies Lawitz E NEJM 2013; Jacobson IM NEJM 2013

15. Patients population with the highest unmet need Cirrhosis Patients without response after previous therapy (double & triple) Patients intolerant to Interferon

16. PROPORTION OF NAÏVE HCV GENOTYPE 1 PATIENTS WITHOUT RESPONSE TREATMENT 0 20 40 60 80 100 SVR (%) PegIFN/RBVBOC or TVR + PegIFN/RBV 38-44 25-37% Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Setting% without Response HCV G1 naive25-37

17. PROPORTION OF EXPERIENCED HCV GENOTYPE 1 PATIENTS WITHOUT RESPONSE AFTER TREATMENT 0 20 40 60 80 100 SVR (%) RelapsersPartial Responders 17-31 PegIFN + RBV Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Vierling JM, et al. AASLD 2011. Abstract 931. Null Responders BOC or TVR + PegIFN + RBV 71-76 41-60 85-93 62-71 5 95 Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders 41-60 HCV G1 null responders63-71

18. 18 HCV Genotype 2 and 3: good results with PEGIFN + RBV but 30-40% without response 0 20 40 60 80 100 25.5 84.7 94.9 261868973n= 0 20 40 60 80 100 19.9 92.2 74.0 2519321161 Virological response (%) 71.4 732 Genotype 2 (n=1025)Genotype 3 (n=1259) 60.6 763 The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR) or 12, or ≥24 weeks after end of treatment (SVR) Week 2Week 4 (RVR) Week 12SVR24Week 2Week 4 (RVR) Week 12SVR24 Primary analysis population Marcellin PM, et al. Hepatology 2012 [Epub ahead of print] Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders 41-60 HCV G1 null responders63-71 HCV G229 HCV G328

19. 19 Virological response : G1 and G4 two genotypes same pitfall of the Standard of Care Genotype 4 (n=317) 70.3 40.4 10.1 0 20 40 60 80 100 32128223130 41.0 0 20 40 60 80 100 Genotype 1 (n=4520) Virological response (%) 6.3 2871200 61.3 2769n= 1891 Week 2Week 4 (RVR) Week 12SVR24 41.8 26.5 Week 2Week 4 (RVR) Week 12SVR24 The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL by week 2, 4 (RVR) or 12, or ≥24 weeks after end of treatment (SVR) Marcellin PM, et al. Hepatology 2012 [Epub ahead of print] Setting% without Response HCV G1 naive25-37 HCV G1 relapsers17-31 HCV G1 partial responders 41-60 HCV G1 null responders63-71 HCV G229 HCV G328 HCV G459

20. Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients With actual treatment options > 40% of patients without response (60% HCV genotype 4 – 30% HCV genotype 2)

21. 84 62/74 93* [2] 38/41 Previous Null Responders: Quad Therapy 100 80 60 40 20 0 SVR12 or 24 (%) 90 [1] 9/10  Quad therapy may be a good option for null responders  Well tolerated BUT cirrhotics excluded *Asunaprevir QD and BID combined. 88% GT1a n/N = 100 80 60 40 20 0 SVR12 (%) 61% GT1a n/N = Daclatasvir (NS5A) + Asunaprevir (PI) + PegIFN/RBV x 24 wks (Quad) Danoprevir/r (PI) + Mericitabine (Nuc) + PegIFN/RBV x 24 wks (Quad) [3] 1. Lok AS, et al. N Engl J Med. 2012;366:216-224. 2. Lok AS, et al. AASLD 2012. Abstract 79. 3. Feld JJ, et al. AASLD 2012. Abstract 81.

22. SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT- 267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY Kowdley KV EASL 2013

23. Simeprevir + Sofosbuvir + RBV Genotype 1 F0-F2 non responders Simeprevir Sofosbuvir RBV Simeprevir Sofosbuvir RBV Simeprevir Sofosbuvir 24 weeks 12 weeks Number24152714 RVR %81668557 UND EOTR8388100 SVR84/6 66%5/5 100%26/27 96%13/14 (92%) Anemia %250110 Bilirubin increase 2020 CAVEAT SVR w8 mild fibrosis Lawitz CROI 2013

24. SVR Daclatasvir + Sofosbuvir + RBV G1 Telaprevir /Boceprevir failure DCV +SOFDCV + SOF + RBV N2120 EOT UNDETECTABLE 21/21 (100%)19/20 (95%) SVR 421/21 (100%)20 (100%) SVR 12 Non cirhosis, breakthrough, relapsers and non responders 1a 80% IL28b; nonCC 98%; > F2 83% Sulkowski EASL 2013

25. Sofosbuvir + Ribavirin in HCV G2 &3 Non responders: Fusion Study HCV genotype 2 or 3 patients who failed prior interferon-based therapy were randomized (1:1) to receive either a 12-week (n=103) or 16-week (n=98) course of sofosbuvir 400 mg once daily plus RBV (1,000 or 1,200 mg/day). 63% HCV genotype 3. 34% Cirrhosis Historical control group: 25% SVR Jacobson IM NEJM 2013 % SVR

26. Patients population with the highest unmet need Cirrhosis Patients without response after triple therapy Patients intolerant to Interferon

27. Gaps in Care Resulting in Low Overall Effectiveness of HCV Treatment in Veterans with Chronic HCV Kramer JR et al, J Hepatol 2011 % of HCV infected Veterans (n = 99,166)

28. Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients Patients w/o response to the most advanced treatment options & patients with genotype 4 with poor response to PEGIFN + RBV HIV+ response  reduced all cause mortality but uncommon with PEGIFN + RIBA, few data with triple therapy Intolerant to interferon  the missed target that could change the landscape

29. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options Suzuki J Hepatol 2013

30. Asunaprevir and Daclatasvir in 22 Japanese HCV G1b ineligible/intolerant to Interferon Daclatasvir and asunaprevir trough plasma concentrations HCV RNA levels, individual patients Suzuki J Hepatol 2013

31. POSITRON Efficacy of a 12-Week of Sofosbuvir Plus Ribavirin for Chronic Hepatitis C Patients HCV G2 or 3 who are Unable or Unwilling to Take Interferon Study population: HCV G2 or G3 were interferon intolerant, interferon ineligible or unwilling to take interferon randomized (3:1) to receive 12 weeks of either sofosbuvir 400 mg once daily plus weight-based RBV twice daily (n=207) or matching placebo (n=71). 207 patients randomized to the sofosbuvir/RBV arm, – 15 percent had compensated cirrhosis (more advanced liver disease) – 53 percent were infected with genotype 2. 0/71 59/97 102/110 Jacobson IM NEJM

32. Patients populations with the highest unmet needs Cirrhosis: – Most urgent need  response = short term survival – Lower rate of response to treatment – Highest rate of side effects: Reasonable in compensated patients w/o advanced disease Chance of death or hospitalization > treatment response in advanced disease Treatment not indicated in decompensated patients Patients w/o response to the most advanced treatment options & patients with genotype 4 with poor response to PEGIFN + RBV HIV+ response  reduced all cause mortality but uncommon with PEGIFN + RIBA, few data with triple therapy Intolerant to interferon  the missed target that could change the landscape

33. The paradox of new anti HCV drugs development Studies mainly in easy to treat populations with the lower urgent need: –HCV G1b –Naives –Non cirrhotics –HIV- Few studies in difficult to treat populations with the most urgent need: –Transplanted patients –Decompensated and compensated cirrhosis –Null responders –HCV G1a –HIV+ Marketing of new anti HCV drugs with high prices  cost effectiveness only in sickest patients without enough data from phase III studies