Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Simeprevir (Olysio) Prepared by: David Spach, MD & H. Nina Kim, MD Last Updated: October 27, 2014

Hepatitis web study Hepatitis web study Background and Dosing S IMEPREVIR (O LYSIO )

Hepatitis web study Simeprevir (Olysio) Summary Approval Status: FDA approved December 6, 2013 Indication for HCV Monoinfection - GT 1: Simeprevir (12 weeks) + peginterferon + ribavirin (12 or 36 weeks) - Poor response to Simeprevir + Peginteferon + Ribavirin with GT1a and NS3 Q80K polymorphism at baseline Class & Mechanism - NS3/4A protease inhibitor - Activity against GT 1,2,4,5,6 (strongest activity against GT 1a, 1b) Simeprevir Dosing mg PO once daily with food - In combination with peginterferon + ribavirin (triple therapy) Adverse Effects (AE) attributable to Simeprevir - Rash (including a photosensitivity reaction), pruritus, and nausea Wholesaler Acquisition Cost in United States - 28 tablet bottle = $22,120; estimated 12-week cost = $66,360

Hepatitis web study HCV Protein Processing Role of Role of NS3/4A Serine Protease Protein Processing C C A A NS2 NS3 E1 p7 E2 B NS5 A A B NS4 NS3/4A Serine Protease C C NS4B NS5A NS2 NS3 E1 NS4 A p7 E2 NS5B Proteins Polyprotein Precursor Signal PeptidaseNS2/3 Protease

Hepatitis web study HCV Protein Processing NS3/4A Serine Protease Inhibition C C A A NS2 NS3 E1 p7 E2 B NS5 A A B NS4 Polyprotein Precursor NS3/4A Serine Protease Simeprevir C C NS2 NS3 E1 p7 E2 Proteins A A B NS5 A A B NS4

Hepatitis web study Hepatitis web study Clinical Trials S IMEPREVIR (O LYSIO )

Hepatitis web study Hepatitis web study Phase 3 Trials in Treatment Naive - QUEST 1: Simeprevir-PEG-RBV vs. PEG-RBV in GT1 - QUEST 2: Simeprevir-PEG-RBV vs. PEG-RBV in GT1 Phase 3 Trials in Treatment Experienced - PROMISE: Simeprevir-PEG-RBV vs. PEG-RBV in GT1, prior relapse Phase 3 Trials in Treatment Naïve and Experienced - C212: Simeprevir in HIV-HCV coinfected in GT1 Phase 3 Trials in Progress - ATTAIN: Simeprevir vs. Telaprevir in prior null or partial responders - RESTORE: Simeprevir in HCV genotype 4 (naïve and experienced) - Phase 3 Trials in Treatment Naive - QUEST 1: Simeprevir-PEG-RBV vs. PEG-RBV in GT1 - QUEST 2: Simeprevir-PEG-RBV vs. PEG-RBV in GT1 Phase 3 Trials in Treatment Experienced - PROMISE: Simeprevir-PEG-RBV vs. PEG-RBV in GT1, prior relapse Phase 3 Trials in Treatment Naïve and Experienced - C212: Simeprevir in HIV-HCV coinfected in GT1 Phase 3 Trials in Progress - ATTAIN: Simeprevir vs. Telaprevir in prior null or partial responders - RESTORE: Simeprevir in HCV genotype 4 (naïve and experienced) - Simeprevir: Summary of Key Phase 3 Clinical Trials

Hepatitis web study Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-1 Trial Phase 3 Treatment Naïve Jacobson IM, et al. Lancet. 2014;384:

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: Simeprevir + PEG + Ribavirin for Treatment-Naïve HCV GT1 QUEST-1 Trial

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: N =130 Placebo + PEG + RBV Simeprevir + PEG + RBV Simeprevir + PEG + RBV N = 264 Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Design PEG + RBV Response-Guided Therapy Patients with HCV RNA <25 IU/ml at week 4 and <15 IU/ml at week 12 completed treatment after 24 weeks. Randomized 2:1; stratified on IL28B and HCV1 subtype Drug Dosing Simeprevir: 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75kg Week

Hepatitis web study Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results QUEST-1: Proportion of Patients with SVR12 Source: Jacobson IM, et al. Lancet. 2014;384: Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin P < /130210/264

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: SVR12 by HCV Genotype 1 Subtype Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results Abbreviations: PEG = Peginterferon RBV = Ribavirin 105/14736/74105/11729/56

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results Abbreviations: PEG = Peginterferon RBV = Ribavirin 31/6016/3073/8619/43

Hepatitis web study Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results SVR12 Response in Simeprevir Arm Based on Achievement of RGT Criteria Source: Jacobson IM, et al. Lancet. 2014;384: RGT= response-guided therapy: in simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks SVR12 Based on Meeting RGTPatients (%) who Met RGT Criteria 203/2246/28 N = 264

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: Abbreviations: PEG = Peginterferon RBV = Ribavirin QUEST 1: SVR12 by Host IL28B Genotype Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results 72/7729/37114/5032/7624/374/17

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: QUEST 1: SVR12 by Liver Fibrosis (Metavir Score) Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results Abbreviations: PEG = Peginterferon RBV = Ribavirin 152/18354/9036/466/2318/315/17

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014;384: Stopping rules: (1) Stop simeprevir or placebo if HCV RNA>1000 at week 4; (2) Stop all therapy if HCV RNA < 2 log 10 IU/mL reduction at week 12; (3) Stop all therapy if HCV RNA ≥25 IU/mL at week 24 or 36. On-treatment failure: Detectable HCV RNA at end of treatment. On-Treatment Failure or Relapse Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results 24/26444/13021/23418/84

Hepatitis web study Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results Emergent Protease Resistance in Patients who Failed to Achieve SVR12 Source: Jacobson IM, et al. Lancet. 2014;384:  Among simeprevir-treated patients who failed to achieve SVR12, emergent mutations in NS3 protease domain detected in 35 (92%) of 38  Genotype 1A: Most common mutation = R155K alone or in combination with mutations at codons 80 and/or 168  Genotype 1B: Most common mutation = D168V

Hepatitis web study Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Adverse Effects Source: Jacobson IM, et al. Lancet. 2014; June 3. [Epub ahead of print]. QUEST 1: EventSimeprevir + PEG + RBV (n=264) Placebo + PEG + RBV (n=130) Discontinuation (due to adverse event) 3%2% Grade 3 adverse event25%33% Grade 4 adverse event3% 5% Fatigue42%41% Headache33%39% Pruritus30%20% Rash (any type) 34%32% Anemia20%21% Photosensitivity condition3%<1% Neutropenia24%18% Bilirubin increase9%5%

Hepatitis web study Source: Jacobson IM, et al. Lancet. 2014; June 3. [Epub ahead of print]. Interpretation: “Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin.” Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Conclusions

Hepatitis web study Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial Phase 3 Treatment Naïve Manns M, et al. Lancet. June 4 [Epub ahead of print]

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Background

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] N =134 Placebo + PEG + RBV Simeprevir + PEG + RBV Simeprevir + PEG + RBV N = 257 Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Design PEG + RBV Drug Dosing Simeprevir: 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week OR Peginterferon alfa-2b: 1.5 mcg/kg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Study Notes  Randomized 2:1, stratified on IL28B and HCV subtype  63% in each arm randomized to receive PEG alfa-2a or PEG alfa-2b; remainder assigned PEG alfa-2a  Response-guided therapy (RGT): In simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks Week

Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results QUEST 2: Proportion of Patients with SVR12 Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] P < Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 67/134209/257

Hepatitis web study QUEST 2: SVR12 by HCV Genotype 1 Subtype Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 86/10726/57123/15041/47 P < /10726/57123/15041/77

Hepatitis web study QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 18/247/1465/7917/40

Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results QUEST 2: SVR12 Response in Simeprevir Arm Based on RGT Criteria Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] RGT= response-guided therapy: in simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks SVR 12 Based on Meeting RGTPatients (%) who Met RGT Criteria 202/2355/16 N = 257

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] QUEST 2: SVR12 by Host IL28B Genotype Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 34/4272/7529/71114/1424/2123/40

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] QUEST 2: SVR12 by Liver Fibrosis (Metavir Score) Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 11/176/15165/19552/10224/369/17 P <

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] SVR12 by Type of Peginterferon Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results Type of PEG: 63% of patients randomized to receive PEG alfa-2a versus alfa-2b; remainder assigned PEG alfa-2a Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 79/10021/4668/7728/4562/8018/43

Hepatitis web study QUEST 2: Patients Who Had On-Treatment Failure or Relapse Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] Abbreviations: PEG = Peginterferon; RBV = Ribavirin On-Treatment Failure: Detectable HCV RNA at end of treatment. Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results 30/23621/8818/25743/134

Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Adverse Effects Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] QUEST 2: EventSimeprevir + PEG/RBV (n=257) Placebo + PEG/RBV (n=134) Discontinuation (due to adverse event) <1% Grade 3 adverse event27%31% Grade 4 adverse event6%4% Headache39%37% Fatigue37%42% Pyrexia31%40% Influenza-like illness26% Rash (any type) 27%20% Pruritus26%27% Photosensitivity reactions4%<1% Anemia21%28% Neutropenia21%27%

Hepatitis web study Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Results QUEST 2: Emergent Resistance in Patients who Failed to Achieve SVR12 Source: Manns M, et al. Lancet. June 4 [Epub ahead of print]  Among simeprevir-treated patients who failed to achieve SVR12, emergent mutations in NS3 protease domain detected in 98%  Genotype 1A: Most common mutation = R155K alone or in combination with mutations at codons 80 and/or 168  Genotype 1B: Most common mutation = D168V and Q80R + D168E

Hepatitis web study Source: Manns M, et al. Lancet. June 4 [Epub ahead of print] Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1 QUEST-2 Trial: Conclusions Interpretation: “Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin.”

Hepatitis web study Hepatitis web study Simeprevir in Genotype 1 (Viral Relapsers) PROMISE Trial Phase 3 Treatment Experienced Forns X, et al. Gastroenterology. 2014;146: e3.

Hepatitis web study Source: Forns X, et al. Gastroenterology. 2014;146: e3. Simeprevir + PEG + Ribavirin for Chronic HCV PROMISE Trial

Hepatitis web study Source: Forns X, et al. Gastroenterology. 2014;146: e3. Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Trial: Design N =133 Placebo + PEG + RBV Simeprevir + PEG + RBV Simeprevir + PEG + RBV N =260 PEG + RBV Drug Dosing Simeprevir: 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg Study Notes  Randomized 2:1, stratified on IL28B and HCV subtype  Response-guided therapy (RGT): In simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks Week

Hepatitis web study Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Trial: Results PROMISE Trial: Proportion of Patients with SVR12 Source: Forns X, et al. Gastroenterology. 2014;146: e3. P < Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 206/26048/133

Hepatitis web study PROMISE Trial: SVR12 by HCV Genotype 1 Subtype Source: Forns X, et al. Gastroenterology. 2014;146: e3. Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 78/11115/54128/14934/79

Hepatitis web study Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Results PROMISE Trial: SVR12 Response in Simeprevir Arm Based on RGT Criteria Source: Forns X, et al. Gastroenterology. 2014;146: e3. RGT= response-guided therapy: in simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks Patient (%) with SVR 12 ResponsePatients (%) who Met RGT Criteria 200/2416/15n = 260

Hepatitis web study Source: Forns X, et al. Gastroenterology. 2014;146: e3. PROMISE TRIAL: SVR12 by Host IL28B Genotype Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 55/6218/34131/16728/8320/313/16

Hepatitis web study Source: Forns X, et al. Gastroenterology. 2014;146: e3. PROMISE Trial: SVR12 by Liver Fibrosis (METAVIR Fibrosis Score) Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Trial: Results Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin 137/16740/9832/443/1529/395/19

Hepatitis web study Patients Who Had On-Treatment Failure or Relapse Source: Forns X, et al. Gastroenterology. 2014;146: e3. Abbreviations: PEG = Peginterferon; RBV = Ribavirin On-Treatment Failure: Detectable HCV RNA at end of treatment. Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Results 36/13346/24945/93 8/260

Hepatitis web study Simeprevir Adverse Effects in PROMISE Trial Source: Forns X, et al. Gastroenterology. 2014;146: e3. PROMISE Trial: EventSimeprevir + PR (n=260) Placebo + PR (n=133) Simeprevir + PR (n=260) Placebo + PR (n=133) First 12 WeeksEntire Treatment Phase AE leading to permanent discontinuation of ≥ 1 drug 1.2% Grade 3 event18.1%18.0%24.2%25.6% Grade 4 event1.9%3.0% Fatigue31.9%42.1%32.3%43.6% Headache31.9%36.1%33.1%36.1% Influenza-like illness29.6%20.3%30.0%20.3% Rash (any type)18.5%14.3%23.1%22.6% Pruritus23.5%16.5%27.7%27.8% Neutropenia14.6%16.5%17.7%21.8% Photosensitivity3.5%0%3.5%0% Anemia10.8%6.0%16.9%20.3%

Hepatitis web study Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Results Emergent Protease Resistance in Patients who Failed to Achieve SVR12 Source: Forns X, et al. Gastroenterology. 2014;146: e3.  Most (90.4%) of simeprevir-treated patients who failed to achieve SVR12 developed emerging mutations in the NS3 protease domain  Genotype 1A: Most common mutation = R155K or D168E, or combination of R155K and mutations at codons 80 and/or 168  Genotype 1B: Most common mutations = D168V or D168A, E, T or E/V or the combinations Q80R + D168E/V, or Q80R + S122T + D168E

Hepatitis web study Source: Forns X, et al. Gastroenterology. 2014;146: e3. Conclusions: “In a Phase 3 trial of patients who had relapsed following interferon-based therapy, addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks.” Simeprevir and Peginterferon plus Ribavirin for Chronic HCV PROMISE Conclusions

Hepatitis web study Hepatitis web study Simeprevir in Treatment –Experienced Genotype 1 ASPIRE Trial Phase 3 Treatment Experienced Zeuzem S, et al. Gastroenterol. 2014;146:

Hepatitis web study Source: Zeuzem S, et al. Gastroenterol. 2014;146: Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Features

Hepatitis web study Source: Zeuzem S, et al. Gastroenterol. 2014;146: Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Design n = 66 Drug Dosing: Simeprevir: 100 or 150 mg once daily; Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg Simeprevir 100 mg Peginterferon + Ribavirin Placebo Simeprevir 150 mg Peginterferon + Ribavirin Simeprevir 100 mg Peginterferon + Ribavirin Simeprevir 150 mg Peginterferon + Ribavirin Simeprevir 100 mg Peginterferon + Ribavirin Simeprevir 150 mg Peginterferon + Ribavirin Placebo Peginterferon + Ribavirin Placebo n = 66 n = 65 n = 68 n = 66 n = 65 n = 66 Week

Hepatitis web study Source: Zeuzem S, et al. Gastroenterol. 2014;146: Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results n = 66 Drug Dosing: Simeprevir: 100 or 150 mg once daily; Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg Simeprevir 100 mg Peginterferon + Ribavirin Placebo Simeprevir 150 mg Peginterferon + Ribavirin Simeprevir 100 mg Peginterferon + Ribavirin Simeprevir 150 mg Peginterferon + Ribavirin Simeprevir 100 mg Peginterferon + Ribavirin Simeprevir 150 mg Peginterferon + Ribavirin Placebo Peginterferon + Ribavirin Placebo SVR 24 = 70% SVR 24 = 62% SVR 24 = 66% SVR 24 = 72% SVR 24 = 61% SVR 24 = 80% SVR 24 = 23% n = 66 n = 65 n = 68 n = 66 n = 65 n = 66 Week

Hepatitis web study Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results ASPIRE: SVR 24, by Treatment Regimen Source: Zeuzem S, et al. Gastroenterol. 2014;146: /66 Simeprevir 100 mg 43/6540/6644/6649/6852/6515/66 Simeprevir 150 mgPlacebo

Hepatitis web study Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results ASPIRE: SVR 24, by Prior Treatment Response Source: Zeuzem S, et al. Gastroenterol. 2014;146: /6643/6540/6644/6649/6852/6515/66

Hepatitis web study Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Results ASPIRE: SVR 24, by Prior Treatment Response and GT 1 Subtype Source: Zeuzem S, et al. Gastroenterol. 2014;146: /6643/6540/6644/6649/6852/6515/66 RelapserPartial ResponderNull Responder

Hepatitis web study Source: Zeuzem S, et al. Gastroenterol. 2014;146: Conclusion: “In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks peginterferon and ribavirin significantly increased rates of SVR at 24 weeks compared with patients given placebo, peginterferon, and ribavirin, and was generally well tolerated.” Simeprevir in Treatment Experienced Genotype 1 HCV ASPIRE Trial: Conclusions

Hepatitis web study Hepatitis web study Simeprevir with Peginterferon and Ribavirin in GT-4 RESTORE Phase 3 Treatment Naïve and Treatment Experienced Moreno C, et al. 49 th EASL. April 2014: Abstract P1319.

Hepatitis web study Source: Moreno C, et al. 49 th EASL. April 2014: Abstract P1319. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Features

Hepatitis web study Source: Moreno C, et al. 49 th EASL. April 2014: Abstract P1319. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Design Simeprevir Peginterferon + Ribavirin Treatment-Naïve or Prior Relapse Week Simeprevir Peginterferon + Ribavirin Simeprevir Peginterferon + Ribavirin Partial Response or Null Response RGT determines if PEG + RBV x 24 or 48 wks Response Guided Therapy (RGT) Criteria: Week 4 HCV RNA < 25 IU/mL (detectable or undetectable) and Week 12 HCV RNA < 25 IU/mL (undetectable) Drug Dosing Simeprevir: 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg

Hepatitis web study Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Results RESTORE: SVR12 by Prior Treatment Status Source: Moreno C, et al. 49 th EASL. April 2014: Abstract P /10729/3519/226/1016/40 Treatment-Experienced Nonresponders Treatment-Naïve & Experienced Relapsers

Hepatitis web study Hepatitis web study Simeprevir + Sofosbuvir

Hepatitis web study Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin in Genotype 1 COSMOS Trial Phase 2a, Treatment Naïve and Treatment Experienced Treatment Naïve and Treatment Experienced Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print].

Hepatitis web study Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Study Features

Hepatitis web study Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Baseline Characteristic Baseline Characteristic (n = 167) Cohorts 1 and 2 Median Age, years (range)57 (27-70) Male, %64 White, %81 Median Body Mass Index (BMI)28 HCV genotype1a= 78%; 1b = 22% IL28B non-CC genotype, (%)86% Mean baseline HCV RNA, log 10 IU/ml6.6 Metavir ScoreF01= 20%; F2=28%; F3 = 28%; F4=25% Previous HCV treatment No response (%) Treatment-naïve (%) 76% 24%

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Design for Cohort 1 Cohort 1: Prior Nonresponders; Metavir Scores F0-F2 Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] SOF + SMV + RBV SOF + SMV N = 14 SOF + SMV N = 27 N = 15 N = 24 Drug Dosing SOF= Sofosbuvir: 400 mg once daily SMP =Simeprevir: 150 mg once daily RBV = Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Week 12 SVR12

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results for Cohort 1 COSMOS (Cohort 1): SVR 12 by Regimen Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin 19/2414/1526/2713/14 24-Week Treatment12-Week Treatment

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Design for Cohort 2 Cohort 2: Treatment Naïve & Prior Nonresponders; Metavir Scores F3-F4 Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] SOF + SMV + RBV SVR12 SOF + SMV N = 14 Drug Dosing Sofosbuvir: 400 mg once daily Simeprevir: 150 mg once daily Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg SOF + SMV N = 27 N = 16 N = 30 SVR Week 12

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results COSMOS (Cohort 2 with F3-F4 Fibrosis): SVR12 by Regimen Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin 28/3016/1625/2713/14 24-Week Treatment12-Week Treatment

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results for Cohort 1 & 2 Cohort 1 & 2: SVR12 Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] 19/24 24-Week Treatment12-Week Treatment 14/1526/2713/1428/3016/1625/2713/1472/8082/87 Overall

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results for Cohort 1 & 2 Cohort 1 & 2: SVR12 (Non-VR excluded analysis*) Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] *Non-VR excluded analysis = SVR12 excludes early discontinuation due to non-virologic reasons or missing data at SVR12 time point 19/2013/1326/2713/1428/2815/1525/2713/1471/7481/84 24-Week Treatment12-Week TreatmentOverall

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Results for Cohort 1 & 2 Impact of Q80K on SVR in Patients with GT1 Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print] *G80K = Gln80Lys 17/1830/3164/6838/4055/6218/1926/2735/37119/13068/7225/3151/58

Hepatitis web study Source: Sulkowski MS, et al. JAMA. 2014;312: Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Interpretation Interpretation: “Combined simeprevir and sofosbuvir was efficacious and well tolerated.”

Hepatitis web study Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Key Points High Rates of SVR even in difficult to treat groups, including patients compensated cirrhosis and prior nonresponse to therapy Rapid virologic response (RVR) did not predict SVR 12 Addition of ribavirin did not clearly improve SVR rates Extending treatment to 24 weeks did not clearly improve SVR rates, except possibly in patients with prior relapse and advanced fibrosis Patients with baseline G80K (Gln80Lys) had high SVR rates, including those with compensated cirrhosis Ribavirin did not significantly impact SVR in patients with baseline G80K Regimen well tolerated: fatigue, headache, and nausea were most common side effect Phase 3 studies underway with simeprevir + sofosbuvir in OPTIMIST program Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print]

Hepatitis web study Hepatitis web study Simeprevir and HIV Coinfection

Hepatitis web study Hepatitis web study Simeprevir in HIV Coinfection, GT-1 C212 Trial Phase 3 Treatment Naïve and Treatment Experienced Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] HIV Coinfection

Hepatitis web study Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Study Features

Hepatitis web study Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Design Simeprevir Peginterferon + Ribavirin Treatment-Naïve or Prior Relapse Simeprevir Peginterferon + Ribavirin Simeprevir Peginterferon + Ribavirin Partial Response or Null Response Response Guided Therapy Drug Dosing Simeprevir: 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg Week

Hepatitis web study Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Results C212: SVR12 by Prior Treatment Status Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Treatment-Experienced 78/10642/5313/157/1016/28

Hepatitis web study Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Results C212: SVR12 by GT1 Subtype and Baseline NS3 Q80K Polymorphism Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] 16/1862/8820/3042/58

Hepatitis web study Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Results C212: SVR12 by Fibrosis Stage and Prior History Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Treatment-Experienced 36/4514/2224/274/77/92/21/22/34/76/10

Hepatitis web study Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Results C212: SVR12 by IL28B Genotype Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Treatment-Experienced 27/2840/5911/1815/1519/278/107/76/6 0/2 1/15/71/24/510/192/4

Hepatitis web study Source: Dieterich D, et al. Clin Infect Dis Sep 5 [Epub ahead of print] Simeprevir + PEG + Ribavirin for HCV-HIV Coinfection Study C212: Conclusions Conclusions: “Simeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection.”

Hepatitis web study Hepatitis web study This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online Hepatitis Web Study Funded by a grant from the Centers for Disease Control and Prevention. This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online Hepatitis Web Study Funded by a grant from the Centers for Disease Control and Prevention.