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

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

PegIFN and RBV remain vital components of HCV therapy-- selected presentations from:

Program Disclosure This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. This program is supported by educational grants from Janssen and Vertex Pharmaceuticals.

Educational Objectives Assess safety profile of peginterferon lambda-1a compared to peginterferon alfa-2a in patients with HCV Evaluate efficacy and safety of direct acting antiviral agents in combination with peginterferon and ribavirin in difficult-to-treat patients with chronic hepatitis C Recognize continuing importance of peginterferon and ribavirin in combination with direct acting antiviral agents in the treatment of chronic hepatitis C

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 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 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 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 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 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 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 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 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