SAVINO BRUNO, MD Director Internal Medicine and Hepatology Unit AO Fatebenefratelli e Oftalmico, Milano

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January 29 th 214 Developed by a select panel of 2 thought leaders: SOVALDI in various combinations is Recommended regimen for treatment of chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection. OLYSIO with peginterferon alfa and ribavirin (PR) is Alternative regimen in select patients (interferon eligible chronic HCV genotype 1 patients with either HCV genotype 1b or HCV genotype 1a infection in whom the Q8K polymorphism is not detected at baseline; treatment naïve chronic HCV genotype 4 patients who are eligible for interferon). ROMA 12 febbraio 214 VICTRELIS with PR along with INCIVEK (telaprevir) with PR are Not Recommended for Chronic HCV genotype 1 patients. PR are Not Recommended for Chronic HCV genotype 2, 3 or 4 patients.

11 st August 214 update Treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver related complications and severe ROMA extrahepatic hepatitis C complications are given high priority 12 febbraio 214

1.Natap.org

1.natap.org

NICE National Institute for Health and Care Exellence Summary of Appraisal Committee s key conclusions 1.3 Simeprevir, in combination with sofosbuvir (with or without ribavirin) is not recommended within its marketing authorisation for treating genotype 1 or 4 chronic hepatitis C. 1.Nice.org

214/15 Treatment Options: Right drug Right patient Key Factors in Deciding to Treat patients with HCV infection Risk of complications (degree of fibrosis and comorbidities) Efficacy, safety, duration, pill burden and dosing frequency of therapies Patient motivation/reluctance Affordability

MILD TO MODERATE FIBROSIS stage 214/15 Treatment Options Right drug Right patient HCV related disease: a condition with a wide heterogeneity of clinical features F 2 Metavir, F2 to 3 Ishak, LSM: 6 KPa < 9.5 Kpa (possible overlap with either less or more severe stage), APRI: <.5 (possible overlap) ADVANCED FIBROSIS stage (F3 Metavir, F3 to 4 Ishak, LSM: 9.5 KPa < 12.5 Kpa (possible overlap wth either less or more severe stage), APRI: >.5 <1.5 (possible overlap) WELL COMPENSATED cirrhosis (early stage: 1) F4 Metavir, F5 to 6 Ishak) or LSM: 12.5 KPa #, usually no clinically significant portal hypertension*: HVPG 6, mmhg < 1 mmhg, no esophageal varices, Child A5, MELD < 1. MARGINALLY COMPENSATED (more severe stage: 2) F4 Metavir, F5 to 6 Ishak or LSM: 12.5 KPa #, with moderate to severe portal hypertension : HVPG 1/12 mmhg, ±esophageal varices, PLT 1 /mm 3, low albumin value, Child A5, A6 rarely B7, MELD 1, in Child A5 severe portal hypertension with still preserved liver function may co exist DECOMPENSATED, Child B7 or more, MELD >15 and/or waiting for OLT for ESLD # Castera L. Gastroenterology 212 *Garcia Tsao G. et al, Hepatology 21 Qamar A. et al, Hepatology 28 Boccaccio V, Bruno S. Liver International 214 updated

MILD TO MODERATE FIBROSIS stage 214 Treatment Options Right drug Right patient HCV related disease: a condition with a wide heterogeneity of clinical features F 2 Metavir, F2 to 3 Ishak, LSM: 6 KPa < 9.5 Kpa (possible overlap with either less or more severe stage), APRI: <.5 (possible overlap) ADVANCED FIBROSIS stage (F3 Metavir, F3 to 4 Ishak, LSM: 9.5 KPa < 12.5 Kpa (possible overlap wth either less or more severe stage), APRI: >.5 <1.5 (possible overlap) WELL COMPENSATED cirrhosis (early stage: 1) F4 Metavir, F5 to 6 Ishak) or LSM: 12.5 KPa #, usually no clinically significant portal hypertension*: HVPG 6, mmhg < 1 mmhg, no esophageal varices, Child A5, MELD < 1. MARGINALLY COMPENSATED (more severe stage: 2) F4 Metavir, F5 to 6 Ishak or LSM: 12.5 KPa #, with moderate to severe portal hypertension : HVPG 1/12 mmhg, ±esophageal varices, PLT 1 /mm 3, low albumin value, Child A5, A6 rarely B7, MELD 1, in Child A5 severe portal hypertension with still preserved liver function may co exist DECOMPENSATED, Child B7 or more, MELD >15 and/or waiting for OLT for ESLD # Castera L. Gastroenterology 212 *Garcia Tsao G. et al, Hepatology 21 Qamar A. et al, Hepatology 28 Boccaccio V, Bruno S. Liver International 214 updated

TVR: SVR in naive patients with mild to moderate fibrosis (ADVANCE, ILLUMINATE, OPTIMIZE) T12(bid)/PR T12(q8h)/PR SVR % 1 9 8 7 6 5 4 3 2 1 8 8 79 78,8 8 n=63 n=58 213/267 3/17 28/262 421/529 F 1 F2 F F2 All patients

SVR according to fibrosis score and historical response in F F2 patients in REALIZE study SVR % 1 9 8 7 6 5 4 3 2 1 Relapsers Partial responders Null responders 86 72 32 41 18 6 144/167 1/38 34/47 3/17 24/59 1/18 Zeuzem S, et al. J Hepatol 211

CONCISE: SVR24 in non-cirrhotic IL28B CC treatmentnaïve patients and relapsers achieving ervr 91/16 48/52 T12/PR12 T12/PR24 Nelson DR, et al. HepDart 213. Abstract 118

SVR by BOC in non cirrhotic patients SVR % 1 9 8 7 6 5 4 3 2 1 96 Naïve 72 Relapser/Partial Responders 89 8 Null Responders 55 37 6/11 14/38 Naïve: 63% of patients on BOC PR RGT vs 38% on PR for 48 weeks achieved SVR (p<.1) Treatment experienced: 59% of patients on BOC PR RGT vs 21% on PR for 48 weeks achieved SVR (p<.1) Early Responders (44%) Late Responders (22%) Poordad F, et al. Bacon BR, et al. NEJM 211. Vierling JM, et al. J Hepatol 214

SVR according to treatment week 8 virologic response* in F F2 SVR (%; 95% CI) 1 9 8 7 6 5 4 3 2 1 86 54 6 F F2 5/78 *Treatment naïve and previous treatment failures combined Undetectable 3 log1 decline and detectable <3 log1 decline and detectable Data on file

SVR at a cutoff of 1, IU/mL at TW8 in the metaanalysis of 5 clinical studies in mild to moderate fibrosis Fibrosis Score* SVR [n/m (%)] TW8 <1 IU/ml TW8 1 IU/ml F/F2 175/144 (76) 13/131 (1) *Subjects in BOC arms from 5 clinical studies Data on file

NEUTRINO: SVR12 by Sofosbuvir + P/R (12 weeks) According to Genotype and Fibrosis Level SVR12 According to Genotype SVR12 According to Fibrosis Level 1 8 89 96 1 1 8 92 p=.96 8 SVR12 (%) 6 4 SVR12 (%) 6 4 2 n/n = 261/292 27/28 7/7 GT 1 GT 4 GT 5,6 2 252/273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. NEJM 213

QUEST 1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance 1 8 82 SMV + P/R P/R 1 8 71 9 SVR12 (%) 6 4 53 58 29 SVR12 (%) 6 4 49 52 2 n/n = 188/229 6/113 18/31 5/17 No Cirrhosis Cirrhosis 2 15/147 36/74 GT 1a Differences in SVR12 by Subgroup (95% CIs) GT 1a/other HCV - With baseline Q8K vs Pbo - Without baseline Q8K vs Pbo GT 1b HCV -1-5 5 1 Favors Placebo Favors SMV 15/117 29/56 GT 1b SMV (n) Pbo (n) 28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 4.3 (25.8-54.8) 42.1 (26.5-57.6) 147 6 86 117 74 74 74 56 Jacobson I, et al. EASL 213

Simeprevir plus PegIFN and Ribavirin in treatment experienced F F2 patients with HCV Genotype 1 infection (the ASPIRE trial) Relapsers Partial responders Null responders SVR 24 (%) 1 9 8 7 92 95 76 79 66 Placebo+PR SMV 1 mg+pr* SMV 15 mg+pr* 6 5 56 53 4 3 2 1 8 23 N= 16 48 52 12 38 48 13 3 29 *duration groups pooled Zeuzem S, et al. Gastroenterology 213

SMV + PR: Week 4 on-treatment response* predicts high SVR rates Patients at Week 4 (%) Patients with SVR12 (%) 12/26 35/521 5/12 7/35 Relapser (PROMISE) Naïve (QUEST 1 & 2) detectable and undetectable 247/26 474/521 21/247 49/474 91 95% of patients had a Week 4 on-treatment response with a high probability of achieving SVR Patients with a Week 4 response 25 IU/mL are unlikely to achieve SVR Discontinuation of treatment is recommended according to US prescribing information in these patients HCV RNA < 25 IU/mL, detectable and undetectable Intent-to-treat population FDA backgrounder for FDA advisory committee meeting October 25 213; Simeprevir US Prescribing information

SVR according to fibrosis score and historical response in HCV G1 F3 patients in TVR trials (ADVANCE, ILLUMINATE, OPTIMIZE, REALIZE) 1 Naïve Relapsers Partial responders Null responders 9 85 SVR % 8 7 6 5 4 68,4 55 39 3 2 1 169/247 53/62 1/18 15/38 Zeuzem S, et al. J Hepatol 211. Zeuzem S, et al. AASLD 213

International EAP TVR: ITT SVR by previous treatment response in 552 F3 patients 1 Naïve Relapsers Partial responders Null responders SVR % 9 8 7 6 5 4 71,7 77,1 58,1 41,2 3 2 1 91/127 162/21 36/62 49/119 Colombo M, et al. J Hepatol 214 in press

Overall SVR by F3 1 8 SVR % 6 4 54 26 2 58/17 6/22 F3 BOC PR PR Vierling JM, Bruno S, et al. J Hepatol, 214

SVR according to treatment week 8 virologic response in F3 patients* SVR (%, 95% CI) 9 8 7 6 5 4 3 85 34 Undetectable 3 log HCV-RNA decline and detectable <3 log HCV-RNA decline and detectable 2 1 4/47 16/47 F3 /5 *Treatment-naïve and previous treatment failures combined Vierling JM, Bruno S, et al. J Hepatol, 214

The importance of TW 8 HCV RNA decline in patients with advanced fibrosis/cirrhosis (F3 and F4 pooled) during BOC therapy 1 p<.1 SVR % 8 6 4 63 2 15/238 /31 1 IU/ml (88%) >1 IU/ml (12%) Vierling JM, Bruno S, et al. J Hepatol, 214

SVR12 overall and according to prior response in 121 F3 patients All patients who received at least one dose of BOC included 7 6 5 61,3% Overall F3 61,7% 61,3% 5,6% 5% 4 37,9% 3 2 1 84/137 29/47 45/89 19/31 58/153 21/42 Relapser Partial responder Null responder Bruno S, et al. JVH in press

SVR12 in 121 F3 according to treatment week 8 virologic response All patients who received at least one dose of BOC included 9 8 7 6 5 4 3 2 1 HCV-RNA Undetectable 8,% SVR 39,7% HCV-RNA Detectable 2,% 6,3% 44 23 55 58 11 35 55 58 PPV=8,% NPV=6.3% No SVR 1 9 8 7 6 5 4 3 2 1 HCV-RNA < 1 UI/mL 67% 67 98 SVR % HCV-RNA > 1 UI/mL 33% 33 98 PPV=67% NPV=1% 1% 13 13 No SVR Bruno S, et al. JVH in press

Simeprevir plus PegIFN and Ribavirin in treatment experienced F3 patients with HCV Genotype 1 infection (the ASPIRE trial) Relapsers Partial responders Null responders SVR 24 (%) 1 9 8 7 6 5 4 3 2 1 79 55 5 5 38 22 13 N= 4 19 11 8 16 1 1 9 8 Placebo+PR SMV 1 mg+pr* SMV 15 mg+pr* *duration groups pooled Zeuzem S, et al. Gastroenterology 213

SVR according to fibrosis score and historical response in HCV G1 F4 patients in TVR trials (ADVANCE, ILLUMINATE, OPTIMIZE, REALIZE) SVR % 1 9 8 7 6 5 4 3 2 1 Naïve 53,5 99/185 Relapsers Partial responders Null responders 84 34 14 48/57 11/32 7/5 Zeuzem S, et al. AASLD 213. Zeuzem S, et al. J Hepatol 211

International EAP TVR: ITT SVR by previous treatment response in 526 F4 patients SVR % 1 9 8 7 6 5 4 3 2 1 Naïve Relapsers Partial responders Null responders 62,8 64,4 53,2 28,6 59/94 94/146 41/77 5/175 Colombo M, et al. J Hepatol 214 in press

Overall SVR by F4 1 8 SVR % 6 4 55 2 17 99/18 6/32 F4 BOC PR PR Vierling JM, Bruno S, et al. J Hepatol, 214

SVR according to treatment week 8 virologic response* in F4 1 9 8 89 Undetectable 3 log HCV-RNA decline and detectable SVR (%, 95% CI) 7 6 5 4 3 35 <3 log HCV-RNA decline and detectable 2 1 4/47 65/73 28/79 /17 *Treatment-naïve and previous treatment failures combined Vierling JM, Bruno S, et al. J Hepatol 214

EoTR, SVR12 and relapse rate overall and in 26 cirrhotic patients All patients who received at least one dose of BOC included Overall F4 8 7 6 5 62% 65% 49% 45% 4 3 2 2% 25% 1 237/381 158/26 188/381 118/26 49/237 4/158 EoTR SVR12 Relapse Bruno S, et al. JVH in press

SVR12 overall and according to prior response in 26 cirrhotic patients All patients who received at least one dose of BOC included 7 6 5 61,3% 61,1% Overall 5,6% F4 44,8% 4 3 2 37,9% 33.3% 1 84/137 55/9 45/89 26/58 58/153 37/111 Relapser Partial responder Null responder Bruno S, et al. JVH in press

SVR12 in 26 F4 according to treatment week 8 virologic response All patients who received at least one dose of BOC included HCV-RNA Undetectable HCV-RNA Detectable HCV-RNA < 1 UI/mL HCV-RNA > 1 UI/mL 8 7 6 5 4 3 2 1 71,9% 68,3% 31,7% 28,1% 71 38 14 135 33 97 14 135 SVR No SVR 1 9 8 7 6 5 4 3 2 1 51,7% 16 24 SVR 9,1% 3 33 48,3% 99 24 9,9% 3 33 No SVR PPV=68,3% - NPV=71,9% PPV=51,7%-NPV=9,9% Bruno S, et al. JVH in press

CUPIC SVR12 rates and safety (ANRS CO2 CUPIC) Undetectable HCV RNA (ITT) n (%) BOC n = 212 TVR n = 299 SVR 12 (Total) 91(43) 155 (52) SVR 12 in relapsers 55/12 (54) 92/124 (74) SVR 12 in partial responders 36/94 (38) 54/135 (4) SVR 12 in null responders /1 () 6/31 (19) SAE 44.3% 53.8% Death 1.4% 2.7% Infections 3.8% 9.7% Hepatic decompensation 4.2% 4.7% Anemia <8g/dl or blood tx 9%/11.8% 12.7%/18% Fontaine H, et al. AFEF 213

Risk-benefit (SAE / SVR 12) ( number of patients ) Risk factors for SAE Albumin 35 g/l Albumin <35 g/l Missing data in 63 patients Platelets count > 1,/mm 3 SAE : 6.2 % SVR >> : 54.9% SAE (36) SAE: 16.1 % SVR: > 29% SAE (31) Platelets count 1,/mm 3 SAE: 12.2 % SVR SVR : > 36.5% SAE (74) SAE: 51.4 % SVR: SAE >> 27% SVR (37) 9% Hezode C, et al. Gastroenterology 214

SVR12 according to on treatment response TELAPREVIR BOCEPREVIR 1 9 8 7 6 5 4 3 2 1 63% 125/198 3/11 RVR P <.1 Fontaine H, France, AFEF 213, 4% NO RVR 1 9 8 7 6 5 4 3 2 1 63% 62/99 29/113 HCV RNA Decline 1log W4 P <.1 26% HCV RNA Decline < 1log W4 RVR W8 P <.1 72% 25% 58/81 33/131 NO RVR W8 6% 4/63 HCV RNA Decline < 3log W8

Simeprevir plus PegIFN and Ribavirin in treatment experienced cirrhotic (F4) patients with HCV Genotype 1 infection (the ASPIRE trial) Relapsers Partial responders Null responders 9 8 7 6 5 4 3 2 1 SVR 24 (%)1 82 7 73 46 31 15 N= 6 1 15 2 13 11 2 11 13 Placebo+PR SMV 1 mg+pr* SMV 15 mg+pr* *duration groups pooled Zeuzem S, et al. Gastroenterology 213

Is there still a role of IFN based triple therapy with first generation PI in patients with mild to moderate fibrosis and comorbities (NULLS EXCLUDED) YES Overall SVR rates quite good, Short duration of treatment in the vast majority of patients Patient s reluctance NO SMV or SOF+IFN soon available Safety profile manageable Approved futility rules useful and externally validated *SOC may be considered in naives LVL RVR after lead in

Is there still a role of IFN based triple therapy with first generation PI in patients with mild to moderate fibrosis and comorbities (NULLS EXCLUDED) YES Overall SVR rates quite good, Short duration of treatment in the vast majority of patients Patient s reluctance NO SMV or SOF+IFN soon available Safety profile manageable Approved futility rules useful and externally validated BASED ON FIRST GENERATION PIs COST *SOC may be considered in naives LVL RVR after lead in

Is there still a role of IFN based triple therapy with first generation PI in patients with advanced fibrosis (F3) and early stage (F4) compensated, NULLS F2 included YES NO Overall SVR rates using early futility not that bad Safety profile quite manageable Approval of all-oral combination soon available Patient s reluctance

Treating vs Deferring IFN based triple therapy in marginally compensated Cirrhotic patients with moderate to severe portalhypertension TREAT Urgency of treatment well established Short-term prognosis worrying DEFER Efficacy, safety, duration of therapy, pill burden and dosing frequency unacceptable Approval of all-oral combination soon available EA program or compassionate use soon available

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