Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 2)

Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 2)

Goals for Hepatitis C Therapy Compared to PegIFN α/rbv, new treatment regimens for chronic hepatitis C should offer: Improved efficacy Efficacy in all patient types including previously treated patients, cirrhotic and black patients Orally effective regimens, IFN free Shorter treatment durations Improved side-effect profiles

Selected Antivirals for the Treatment of Chronic Hepatitis C, 2012 New agents covered in this presentation, all in Phase 3 trials Compound Sponsor Activity Peginterferon Lambda-1a Sofosbuvir (GS-7977) Simeprevir (TMC435) Bristol-Myers Squibb Gilead Janssen Type III interferon immune modulator Uridine nucleotide analog NS5B polymerase inhibitor NS3/4A protease inhibitor

Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Peginterferon Lambda 1a (Lambda) Compared to Peginterferon Alfa 2a (Alfa) in Treatment Naïve Patients With HCV Genotypes (GT) 1 or 4: SVR24 Results From EMERGE Phase 2b Muir AJ, Hillson JL, Gray TE, Xu D, Ishak L, Freeman JA, Fontana D, Horga A, Lopez-Talavera JC Abstract 214, AASLD 2012

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Objective: To investigate efficacy and tolerability of PegIFN lambda-1a (Lambda) compared to the efficacy and tolerability of PegIFN alfa-2a (Alfa) in treatment-naïve patients with HCV genotypes 1 or 4 Lambda is a pegylated type III interferon that exerts antiviral effects through a unique receptor with limited distribution outside the liver Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Methods 407 non-cirrhotic, treatment-naïve patients infected with HCV GT1: N=384 GT4: N=23 Treatment: Lambda: 120, 180, or 240 μg weekly Alfa: 180 μg weekly All patients received daily ribavirin Treatment duration: 48 weeks Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Efficacy HCV RNA <LLOQ (% patients) 100 80 60 40 58.2 55.9 57.8 55.1 56.7 55.8 56.3 45.9 37.3 39.4 RVR (Week 4) cevr (Week 12 ETR (Week 48) SVR24 (Week 72) 36.9 36.9 20 14.7 16.3 6.1 5.8 0 Lambda 120 ug + RBV (N=98) Lambda 180 ug + RBV (N=102) Lambda 240 ug + RBV (N=104) Alfa 180 ug + RBV (N=103) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients HCV RNA concentration over time Lambda 120 g Lambda 180 g Lambda 240 g Alfa-2a 180 g Lambda is asociated with a faster decline in HCV RNA levels Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Safety Results: Adverse Events Adverse Events n (%) Lambda 120 μg N=98 Lambda 180 μg N=102 Lambda 240 μg N=104 Alfa 180 μg N=103 Serious adverse events 6 (6.1) 3 (2.9) 9 (8.7) 7 (6.8) IFN dose reductions 6 (6.1) 8 (7.8) 76 (73.1) 29 (28.2) RBV dose held/reduced 11 (11.2) 11 (10.8) 12 (11.5) 34 (33.0) Flu-like symptoms (pyrexia, chills, or pain) Musculoskeletal (arthralgia, myalgia, or back pain) 17 (17.3) 13 (12.7) 8 (7.7) 47 (45.6) 21 (21.4) 16 (15.7) 22 (21.2) 48 (46.6) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Safety Results: Laboratory Values Laboratory Abnormalities n (%) Hemoglobin <10 g/dl or >3.4 g/dl below baseline Lambda 120 μg N=98 Lambda 180 μg N=102 Lambda 240 μg N=104 Alfa 180 μg N=103 27/97 (27.8) 23/101 (22.8) 19/102 (18.6) 64/103 (62.1) Neutrophils <1000/mm 3 1/97 (1.0) 2/101 (2.0) 1/102 (1.0) 44/103 (42.7) Platelets <100,000/mm 3 0 2/101 (2.0) 0 20/103 (19.4) ALT >5xULN 1/98 (1.0) 1/101 (1.0) 10/102 (9.8) 4/103 (3.9) Direct bilirubin >1.2 mg/dl 0 5/101 (5.0) 13/102 (12.7) 2/103 (1.9) Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

PegIFN Lambda-1a vs. PegIFN Alfa-2a in Treatment- Naïve Genotype 1 or 4 HCV Patients Conclusions Compared to Alfa, treatment with Lambda is associated with comparable efficacy in non-cirrhotic patients chronically infected with HCV GT1 or 4 Patients treated with Lambda experienced less hematologic toxicity and fewer musculoskeletal and flulike symptoms Improved safety profile supports further evaluation of Lambda in combination with direct-acting antiviral agents Muir AJ et al. Hepatology 2012; 56(Suppl S1):299A

Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Once Daily Sofosbuvir (GS-7977) plus PEG/RBV: High Early Response Rates Are Maintained During Post-Treatment Follow-Up In Treatment-Naïve Patients With HCV Genotype 1, 4, and 6 Infection in the ATOMIC Study Hassanein T, Lawitz E, Crespo I, Davis M, DeMicco MP, Nelson DR, Bernstein DE, Afdhal N, Jacobson IM, Vierling JM, Gordon SC, Anderson J, Hyland RH, Hindes R, Symonds WT, Albanis E, Arora S, Kowdley KV Abstract 230, AASLD 2012

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Objective To determine the optimal duration of treatment for the uridine nucleotide analog sofosbuvir (SOF, formerly GS- 7977) 400 mg once daily combined with pegylated interferon alfa-2a (PEG) and ribavirin (RBV) in treatment naïve patients chronically infected with HCV genotypes 1, 4, or 6 Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Study Design Day 1 Wk 12 Wk 24 Group A N=52 SOF + PEG + RBV GT1 Group B N=125 SOF + PEG + RBV GT1, 4, 6 Group C N=155 SOF + PEG + RBV SOF (n=75) SOF + RBV (n=75) GT1 Non-cirrhotic, treatment-naive patients with with genotype 1 were randomized 1:2:3 into open-label arms *Of the 125 patients enrolled in Arm B, 11 were genotype 4 and 5 were genotype 6 Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Efficacy overall 100 98% 94% 94% 90% 98% 99% 94% 92% 97% 99% 93% 91% Week 4 EOT Patients with HCV RNA <LOD (%) 80 60 40 SVR4 SVR12 20 0 SOF+PEG+RBV 12 Wks SOF+PEG+RBV 24 Wks SOF+PEG+RBV 12+12 Wks Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Efficacy in Genotype 4 and 6 Patients with HCV RNA <LOD (%) 100 80 60 40 100% 100% 100% 100% 100% 82% 82% 100% Week 4 EOT SVR4 SVR12 20 0 GT4 (n=11) SOF+PEG+RBV 24 Wks GT6 (n=5) SOF+PEG+RBV 24 Wks Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Adverse Events Sofosbuvir + PEG+RBV 12 wks (n=52) Sofosbuvir + PEG+RBV 24 wks (n=125) Sofosbuvir + PEG+RBV 12 wks + 12 wks (n=155) Serious AEs, n (%) 2 (4) 6 (5) 4 (3) AEs leading to d/c of any drug, n (%) 3 (6) 20 (16) 7 (5) Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Adverse Events Most common AEs (>15%, overall) n (%) Sofosbuvir + PEG+RBV 12 wks (n=52) Sofosbuvir + PEG+RBV 24 wks (n=125) Sofosbuvir + PEG+RBV 12 wks + 12 wks (n=155) Fatigue 25 (48) 63 (50) 86 (55) Headache 14 (27) 38 (30) 65 (42) Nausea 16 (31) 43 (34) 51 (33) Insomnia 12 (23) 28 (22) 36 (23) Anemia 7 (13) 31 (25) 34 (22) Rash 7 (13) 26 (21) 39 (25) Chills 15 (29) 25 (20) 29 (19) Neutropenia 12 (23) 25 (20) 22 (14) Pyrexia 18 (35) 15 (12) 26 (17) Decreased Appetite 7 (13) 17(14) 34 (22) Diarrhea 11 (21) 23 (18) 20 (13) Arthralgia 15 (29) 23 (18) 14 (9) Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Grade 3 Hematology and Chemistry Laboratory Abnormalities in >1% of Patients Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A Sofosbuvir + PEG+RBV 12 wks (n=52) Sofosbuvir + PEG+RBV 24 wks (n=125) Sofosbuvir + PEG+RBV 12 wks + 12 wks (n=155) Hemoglobin decreased 3 (6) 8 (6) 11 (8) WBCs decreased 6 (11) 9 (7) 4 (3) Lymphocytes decreased 3 (6) 14 (11) 3 (2) Neutrophils decreased 13 (25) 27 (22) 27 (17) Platelets decreased 2 (4) 1 (<1) 1 (<1) AST 2 (4) 4 (3) 2 (1) ALT 2 (4) 0 2 (1) Hyperglycemia 0 2 (2) 5 (3) Lipase 2 (4) 2 (2) 1 (<1)

ATOMIC Trial Update: Sofosbuvir (GS-7997) + PEG/RBV in Genotypes 1, 4, and 6 HCV Follow-up Conclusions Sofosbuvir 400 mg once daily + PEG/RBV for 12 weeks appears to be safe and highly effective for the treatment of patients with HCV genotype 1 12 weeks of sofosbuvir + PEG/RBV was as effective as 24 weeks of therapy in patients with HCV genotype 1 24 weeks of sofosbuvir 400 mg once daily + PEG/RBV appears to be highly effective in HCV genotype 4 and 6 Hassanein T et al. Hepatology 2012; 56(Suppl S1):307A

Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Efficacy and Tolerability of TMC435 150 mg Once Daily with Peginterferonα-2a and Ribavirin for Treatment of HCV Genotype 1 Infection in Patients with Metavir Score F3 and F4 (Pillar and Aspire Trials) Poordad F, Fried MW, Zeuzem S, Ferenci P, Lenz O, Sinha R, Callewaert K, Peeters M, Beumont M Abstract 83, AASLD 2012

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Objective To assess efficacy and safety of treatment with simeprevir (TMC435)/PegIFN/RBV vs. placebo/pegifn/rbv in F3/F4 treatment-naïve and treatment-experienced HCV patients Simeprevir is a NS3/4 protease inhibitor Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Methods Post hoc analysis performed to evaluate efficacy and safety/tolerability in F3/F4 patients in PILLAR and ASPIRE trials Simeprevir 150 mg dose groups only Simeprevir treatment duration groups pooled Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Study Design PILLAR: Treatment-naïve patients (including F3) SMV + PR Pbo + PR PR Post-therapy FU SMV + PR PR Post-therapy FU Pbo + PR PR Post-therapy FU RGT in SMV arms ASPIRE: Treatment-experienced patients (prior relapsers, partial and null responders including F3 and F4) SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Poordad F et al. Hepatology 2012; 56(Suppl S1):233A Post-therapy FU Post-therapy FU 75 mg, n=78 150 mg, n=77 75 mg, n=75 150 mg, n=79 Control, n=77 100 mg, n=66 150 mg, n=66 100 mg, n=65 150 mg, n=68 100 mg, n=66 150 mg, n=65 Control, n=66 0 12 24 48 72 Weeks

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy 100 80 71% 79% Placebo/ PR Simeprevir 150 mg/pr SVR24 (%) 60 40 56% 62% 20 0 5/7 15/19 PILLAR treatmentnaïve: F3 4% 1/23 ASPIRE treatmentexperienced: F3/F4 pooled 0 38/68 0/10 24/39 ASPIRE treatmentexperienced: F4 only Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy: Response-guided therapy* in treatment naïve F3 patients 84% (16/19) met RGT* criteria and ended treatment at week 24 100 80 Simeprevir 150 mg/pr 94% SVR24 (%) 60 40 *Response-guided therapy (RGT) criteria in simeprevir arms: End treatment at wk 24 if HCV RNA <25 IU/mL at wk 4 and undetectable at wks 12, 16 and 20; all other patients continued PR up to wk 48 20 0 15/16 PILLAR patients who met RGT Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Efficacy: Treatment-experienced SVR 24 by prior response to PegIFN/RBV in F3/F4 patients 100 SVR24 (%) 80 60 40 65% 67% 33% 20 0 10% 0/10 17/26 1/10 14/21 0/3 17/21 Relapser Partial Responder Null Responder 31% (4/13) null responders with cirrhosis (F4) achieved SVR24 Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Adverse events: Treatment-naïve and -experienced (pooled data) Proportion of patients with AEs over entire treatment phase, % F3/F4 patients Pbo PR (n=30) SMV 150 mg PR (n=87) F0-F2 patients Pbo PR (n=113) SMV 150 mg PR (n=267) Any AE 97 99 97 99 Grade 3/4 AEs 27 43 32 35 Serious AEs 10 8 10 8 SMV/pbo discontinuation due to AE 0 9 8 8 Death due to AE 0 0 0 0.4 *AEs listed do not include changes in laboratory parameters Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Adverse events:* Treatment-naïve and -experienced (pooled data) Most common AEs (<25% in F3/F4 SMV patients) *AEs listed do not include changes in laboratory parameters Poordad F et al. Hepatology 2012; 56(Suppl S1):233A F3/F4 patients Pbo PR (n=30) SMV 150 mg PR (n=87) F0-F2 patients Pbo PR (n=113) SMV 150 mg PR (n=267) Fatigue 57 55 43 39 Influenza-like illness 27 26 30 26 Asthenia 13 26 18 22 Pruritus 40 41 30 33 Dry Skin 23 31 15 18 Rash 33 30 15 18

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Laboratory toxicities: Treatment-naïve and -experienced (pooled data) Proportion of patients with toxicities over entire treatment phase, % Hemoglobin At least Grade 2 (<9.5 g/dl) Grade 3 (6.5-7.9 g/dl) Grade 4 (<6.5 g/dl) Absolute neutrophil count Grade 3 (500-749/mm 3 ) Grade 4 (<500/mm 3 ) Platelets Grade 3 (20,000-9,000/mm 2 ) Grade 4 (<20,000/mm 2 ) F3/F4 patients Pbo PR (n=30) 27 3 0 27 3 3 0 SMV 150 mg PR (n=87) 16 2 0 28 5 8 0 F0-F2 patients Pbo PR (n=113) 11 2 0 25 4 3 1 SMV 150 mg PR (n=267) 9 0.4 0 29 7 1 0 Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Laboratory toxicities: Treatment-naïve and -experienced (pooled data; cont) Proportion of patients with toxicities over entire treatment phase, % F3/F4 patients Pbo PR (n=30) SMV 150 mg PR (n=87) F0-F2 patients Pbo PR (n=113) SMV 150 mg PR (n=267) Creatinine Grade 3 or 4 (>3.0 x ULN) 0 0 0 0 Total bilirubin Grade 3 (>2.5-5.0 x ULN) Grade 4 >5.0 x ULN) 3 0 7 0 1 0 6 1 Majority of laboratory abnormalities were mild/moderate Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

PILLAR and ASPIRE Trials: Efficacy and Safety of Simeprevir/PegIFN/RBV in HCV Patients with Advanced Liver Disease Conclusions Excellent SVR24 rates were obtained with simeprevir 150 mg combined with PegIFN/RBV in HCV genotype 1-infected, treatment naïve and - experienced patients Majority of treatment-naive patients were eligible for 24 week treatment duration and achieved >90% SVR24 F3/F4 null responders achieved 33% SVR24 Simeprevir/PegIFN/RBV has a favorable overall safety and tolerability profile Poordad F et al. Hepatology 2012; 56(Suppl S1):233A

Emerging Therapies for HCV: Highlights from AASLD 2012 November 9-13, 2012 Boston, MA Safety and Tolerability of TMC435 in Combination with Peginterferon α-2a and Ribavirin for Treatment of HCV Genotype 1 Infection in Treatment-Naïve and -Experienced patients (PILLAR and ASPIRE Trials) Fried MW, Poordad F, Zeuzem S, Ferenci P, Lenz O, Ouwerkerk-Mahadevan S, Peeters M, Sinha R, Beumont M Abstract 769, AASLD 2012

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Objective To assess safety and tolerability of simeprevir 150 mg in combination with PegIFNα-2a and RBV for the treatment of HCV genotype 1 in treatment-naïve and treatmentexperienced patients (PILLAR and ASPIRE trials) Simeprevir (TCM435) is an NS3/4A HCV protease inhibitor Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Methods Patients received simeprevir 75, 100 or 150 mg QD for 12, 24 or 48 weeks in combination with PegIFN/RBV for 24 or 48 weeks, or placebo/pegifn/rbv for 48 weeks (control) In PILLAR, response-guided therapy criteria were used to determine total treatment duration in simeprevir arms; treatment ended at week 24 if HCV RNA <25 IU/mL detectable/ undetectable at week 4 and <25 IU/mL undetectable at weeks 12, 16, and 20; all other patients continued PegIFN/RBV up to 48. Safety was evaluated with a pooled analysis of patients receiving simeprevir 150 mg QD (n=355) compared to control groups (n=143) Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and-experienced HCV 1 Patients Study Design PILLAR: Treatment-naïve patients (including F3) SMV + PR Pbo + PR PR Post-therapy FU SMV + PR PR Post-therapy FU Pbo + PR PR Post-therapy FU RGT in SMV arms ASPIRE: Treatment-experienced patients (prior relapsers, partial and null responders including F3 and F4) SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU SMV + PR Pbo + PR Post-therapy FU Post-therapy FU 75 mg, n=78 150 mg, n=77 75 mg, n=75 150 mg, n=79 Control, n=77 100 mg, n=66 150 mg, n=66 100 mg, n=65 150 mg, n=68 100 mg, n=66 150 mg, n=65 Control, n=66 0 12 24 48 72 Weeks Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Occurrence of AEs* Proportion of patients, % PILLAR and ASPIRE combined: First 12 weeks Pbo PR (n=143) SMV 150 mg PR (n=355) PILLAR and ASPIRE combined: Overall treatment duration Pbo PR (n=1433) SMV 150 mg PR (n=355) Grade 3/4 AEs 18 21 31 36 Serious AEs 5 5 6 9 AEs leading to SMV/placebo discontinuation AEs leading to discontinuation of any study drug 1 3 2 5 5 5 9 9 *AEs listed do not include changes in laboratory parameters Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Occurrence of AEs* (cont) AEs most frequently reported (>25% patients in pooled overall SMV 150 mg group ), % PILLAR and ASPIRE combined: First 12 weeks Pbo PR (n=143) SMV 150 mg PR (n=355) PILLAR and ASPIRE combined: Overall treatment duration Pbo PR (n=1433) SMV 150 mg PR (n=355) Fatigue 43 39 46 43 Influenza-like illness 29 26 29 26 Pruritus (all types) ǂ 25 33 34 37 Headache 41 40 45 41 Nausea 24 24 25 26 *AEs listed do not include changes in laboratory parameters Treatment arms with different durations combined ǂ All types of rash or pruritus combined Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Occurrence of AEs* (cont) AEs of clinical interest (regardless of causality), % PILLAR and ASPIRE combined: First 12 weeks Pbo PR (n=143) SMV 150 mg PR (n=355) PILLAR and ASPIRE combined: Overall treatment duration Pbo PR (n=1433) SMV 150 mg PR (n=355) Rash (all types) ǂ 16 23 24 29 Rash (all types) ǂ, Grade 3 0 0 0 1 Rash (all types) ǂ, Grade 4 0 0 0 0 Anemia, at least Grade 2 6 4 11 11 Neutropenia TBC TBC 19 26 *AEs listed do not include changes in laboratory parameters These AEs are documented with other agents in the protease inhibitor class ǂ All types of rash or pruritus combined Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in hemoglobin over study period* Mean SE of Actual Values of Hgb (g/dl) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in neutrophils over study period* Mean SE of Actual Values of Neutrophils (giga/l) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in platelets over study period* Mean SE of Actual Values of Platelets (giga/l) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Change in total bilirubin over study period* Mean SE of Actual Values of Total Bilirubin (mg/dl) *Simeprevir 150 mg/pr or Placebo/PR in PILLAR and ASPIRE Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PILLAR and ASPIRE Trials: Safety and Tolerability of Simeprevir/PegIFN/RBV for Treatment-Naive and -Experienced HCV 1 Patients Conclusions Simeprevir 150 mg with PegIFN/RBV was generally well tolerated by both treatment-naïve and treatment-experienced patients in the PILLAR and ASPIRE trials Incidence of AEs, including serious AEs, was comparable between simeprevir-treated patients and PegIFN/RBV control groups There was no difference in mean change over time in hemoglobin, platelets or neutrophils during treatment, between simeprevir and control patients Transporter-mediated bilirubin elevations observed with simeprevir were mild, transient, and reversible Fried MW et al. Hepatology 2012; 56(Suppl S1):563A.

PegIFN and RBV remain vital components of HCV therapy Summary Improved safety profile supports further evaluation of PegIFN Lambda in combination with direct-acting antiviral agents for the treatment of chronic hepatitis C Sofosbuvir 400 mg once daily + PEG/RBV for 12 weeks appears to be safe and highly effective for the treatment of patients with HCV genotype 1; 24 weeks of sofosbuvir 400 mg once daily + PEG/RBV appears to be highly effective in HCV genotype 4 and 6

PegIFN and RBV remain vital components of HCV therapy Summary (cont) Excellent SVR24 rates were obtained with simeprevir 150 mg combined with PegIFN/RBV in HCV genotype 1- infected, treatment naïve and -experienced patients; majority of treatment-naive patients were eligible for 24 week treatment duration and achieved >90% SVR24 PegIFN and RBV when combined with DAA agents will continue to be important components of the HCV treatment armamentarium To treat now or to wait optimal decision-making requires knowledge of current developments