1. Traitement de l’Hépatite C Sans Interféron Patrick Marcellin

2. Hepatitis C

3. Where we are: The achievements

4. Hepatitis C: progress is accelerating  Cure = 100% in 10 years The conclusion of the PHC 2009

5. Progress is accelerating Earlier ? 2015 ?

6. Where we are Better understanding of therapeutic targets Protease Inhibitors Polymerase Inhibitors NS5A Inhibitors

7. Where we are Better efficacy with triple therapy (G1) 20 40 60 80 2002 BI 2012 TRI 0 70% 40% +30% Jacobson et al. NEJM 2012 Poordad NEJM 2012

8. SVR = CURE  Undetectable HCV RNA in serum: 100%  Undectable HCV RNA in liver: ≈100%  Undectable HCV RNA in PBMCs: 100% Marcellin et al. Annals of Intern Madicine 1997 Maylin et al. Gastroenterology 2009

9. Cure = improved prognosis HCC in 300 cirrhotics Cardoso et al. J Hepatol 2010 0 0.2 0.4 0.6 0.8 1.0 SVR (+) SVR (-) p < 0.001 246812 Time since last treatment (years) 10 0

10. Cure = improved prognosis Survival in 300 cirrhotics 0 0,2 0,4 0,6 0,8 1,0 SVR (+) SVR (-) p < 0.001 246810 Time since last treatment (years) 0,0 Cardoso et al. J Hepatol 2010

11. Reinforced screening and access to therapy= decrease in HCV-related mortality Deuffic-Durban et al. EASL 2011 Percentage of decreased mortality modelisation 2012 – 2021 France PEG-IFN + RBV Tritherapy PEG IFN + RBV + PI Tritherapy + reinforced screening + improved access to therapy 0 20 40 60 80 100 - 83 % - 19 % %

12. Where we are: the limitations

13. Where we are: limitations Insufficient screening Undiagnosed Pool 2.5 million Diagnosed Pool 0.9 million Undiagnosed Pool 1.8 million Diagnosed Pool 1.6 million

14. Where we are: limitations 170 million people HCV infected worldwide US 4M Brazil 7M Europa 5M Russia 3M Egypt 12M India 10M China 43M Korea 1M Japan 2M Vietnam 7M Pakistan 9M

15. Where we are: limitations Insufficient access to treatment

16. Where we are: limitations Access to treatment: the bottle necks DiagnosedManagedTreatedCured

17. Where we are: limitations US 4M Brazil 7M Europa 5M Russia 3M Egypt 12M G4 India 10M G3 China 43M Korea 1M Japan 2M Vietnam 7M G6 Pakistan 9M G3 High prevalence of G non1 in high prevalence countries

18. Where we are: The hope is becoming reality

19. Ideal Therapy  100% efficacy  IFN-free  All oral  Short duration  No resistance  Pan-genotypic  Well tolerated and safe  Low cost

20. Where we go Lok et al. NEJM 2012 0 20 40 60 80 100 BMS-790052 + BMS-650032 + PEG IFN + RBV 36 90 % BMS-790052 + BMS-650032 Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PI in G1 null responders: IFN free

21. danoprevir + mericitabine + ribavirine in non responders G 1 n/N Partial RespondersNull Responders % Feld JJ, AASLD 2012 39 55 0 20 40 60 80 100 17/319/23 SVR 12

23. IFN-free ongoing trials: summary First drug (company)Second drugThird drugFourth drug Boehringer ingelheim Faldaprevir (BI201335) BI207127Ribavirin Protease inhibitorNS5B NNI Abbott ABT-450/rABT 267ABT 333Ribavirin Protease inhibitorNS5B NNINS5A inhibitor Gilead/BMSRibavirin Sofosbuvir (GS 7977)GS 5885 NS5B NINS5A inhibitor BMS AsunasprevirDaclastavir+ Ribavirin Protease inhibitorNS5A inhibitor Vertex TelaprevirVX 222Ribavirin Protease inhibitorNS5B

24. 0 500 1000 1500 2000 2500 3000 1980198519901995200020052010201520202025 Years incidence annuelle de la mortalité liée au VHC Without treatment With bitherapy PEG IFN + RBV -14% -32% G1/4 G2/3 Impact of treatment on mortality Deuffic-Durban et al. J Hepatol 2007

25. Reinforced screening and access to therapy= decrease in HCV-related mortality Deuffic-Durban et al. EASL 2011 PEG-IFN + RBV Tritherapy PEG IFN + RBV + PI Tritherapy + reinforced screening + improved access to therapy Percentage of decreased mortality modelisation 2012 – 2021 France 0 5 10 15 20 25 + 83 % + 19 %

26. Where we go: IFN free Therapy

27. Where we go Lok et al. NEJM 2012 0 20 40 60 80 100 BMS-790052 + BMS-650032 + PEG IFN + RBV 36 90 % BMS-790052 + BMS-650032 Quadruple therapy: PEG-IFN+ RBV+ NS5AI + PI in G1 null responders: IFN free

28. danoprevir + mericitabine + ribavirine in non responders G 1 n/N Partial RespondersNull Responders % Feld JJ, AASLD 2012 39 55 0 20 40 60 80 100 17/319/23 SVR 12

29. Faldaprevir + BI 207127 + RBV (naive G1) Zeuzem S, et al. Gatroenterology 2011 40 67 73 82 100 0 20 40 60 80 100 Day 15Day 22Day 29 Patients with HCV RNA <25 IU/mL (%) 400 mg TID BI 207127 + BI 201335 + RBV 600 mg TID BI 207127 + BI 201335 + RBV 6/1514/1717/1710/1511/1517/17

30. ABT-450/r + ABT-333 + ABT-267 + RBV Kowdley et al. AASLD 2012 SVR 12 (ITT) 8W Naîve patient 12W Naïve Patients 12W Null Responders 0 20 40 60 80 100 87 85 98 89 93 SVR 12 (ITT)

31. Sofosbuvir (GS 7977) + GS 5885 + RBV Gane et al. AASLD 2012 HCV RNA < 15 UI/ml SOF + RBV 0 20 40 60 80 100 88 10 100 NaiveNull responders SOF + GS-5885 + RBV NaiveNull responders

32. Faldaprevir + BI 207127 + RBV (naive G1) Zeuzem S, et al. Gatroenterology 2011 40 67 73 82 100 0 20 40 60 80 100 Day 15Day 22Day 29 Patients with HCV RNA <25 IU/mL (%) 400 mg TID BI 207127 + BI 201335 + RBV 600 mg TID BI 207127 + BI 201335 + RBV 6/1514/1717/1710/1511/1517/17

33. ABT-450/r + ABT-333 + ABT-267 + RBV Kowdley et al. AASLD 2012 SVR 12 (ITT) 8W Naîve patient 12W Naïve Patients 12W Null Responders 0 20 40 60 80 100 87 85 98 89 93 SVR 12 (ITT)

34. Sofosbuvir (GS 7977) + GS 5885 + RBV Gane et al. AASLD 2012 HCV RNA < 15 UI/ml SOF + RBV 0 20 40 60 80 100 88 10 100 NaiveNull responders SOF + GS-5885 + RBV NaiveNull responders

35. The Proof of Concept 100% efficacy All oral IFN-free Short duration No resistance Pan-genotypic Well tolerated and safe Low cost ? ?

36. Hepatitis C: progress is accelerating  Cure = 100% in 2-3 years  One pill a day The conclusion of the PHC 2009

37. Where we are: limitations Insufficient access to treatment