Program Disclosure. Provider is approved by the California Board of Registered Nursing, Provider #13664, for 1.5 contact hours.

Transcription

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2 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 joint-sponsorship of the Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. The Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. The Annenberg Center for Health Sciences at Eisenhower designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credits commensurate with the extent of their participation in the activity. Annenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. A maximum of 1.5 contact hours may be earned for successful completion of this activity. Provider is approved by the California Board of Registered Nursing, Provider #13664, for 1.5 contact hours.

3 Learning Objectives Recognize the clinical trial data, AASLD treatment guidelines and approved product labeling for available therapies. Identify patients who are good candidates for currently available therapy versus those patients that would benefit more from future therapies. Use the knowledge gained to maximize clinical outcomes on a case-by-case basis.

4 Case 1

5 Patient Characteristics (June 2014) 52 year old African American male Chronic hepatitis C (CHC) diagnosed in 2012 History/risk factors BMI=35 Diabetes mellitus Moderate drinker/cigarette smoker

6 Results at Time of Diagnosis (June 2012) Genotype IL28B METAVIR (biopsy) BL viral load 1b TT F2 5,100,000 IU/mL In June 2012, decision was made to wait for future therapies

7 Current Labs (June 2014) Hemoglobin 14.6 g/dl Neutrophils 1,100 cells/mm 3 Platelets 210,000 cells/mm 3 ALT Albumin Bilirubin 84 IU/L 4.0 g/dl 0.7 mg/dl

8 Discussion How would you manage this patient today? Do you require additional information? If so, what? What are the most important factors influencing your decision?

9 What Treatment Options Are Available Now?

10 Boceprevir or Telaprevir + PEG/RBV Approved Regimen for GT 1 (Not advised in AASLD/IDSA Guidance Document)

11 First Direct Acting Antivirals (DAAs) for the Treatment of GT 1 Chronic Hepatitis C Boceprevir and telaprevir were approved in 2011 Both compounds act by inhibiting HCV nonstructural NS3/4A protease Major advancement over PEG/RBV In 2014, use of boceprevir and telaprevir not recommended in AASLD/IDSA guidance document Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.

12 Limitations of Boceprevir and Telaprevir Telaprevir and boceprevir only approved for GT 1 Interferon and ribavirin backbone required Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir Response guided therapy (both) and lead-in (boceprevir) complicated week total treatment duration Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans) Hematologic (both) and rash/dermatological (telaprevir) adverse events Drug-drug interactions Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, September 2013.

13 Simeprevir/PEG/RBV Approved Regimen for GT 1 with Certain Limitations

14 Simeprevir (SMV) (TMC 435) FDA approval: November 22, 2013 NS3/4A protease inhibitor One capsule taken once daily with food Approved for GT 1 infected subjects with compensated liver disease (including cirrhosis) Alternative therapy according to AASLD/IDSA guidance document Simeprevir (OLYSIO ) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

15 QUEST 1, QUEST 2 and PROMISE Study Designs Response Guided Treatment SMV 150mg/ PEG/RBV* PEG/RBV PEG/RBV Post-Therapy Follow-Up Post-Therapy Follow-Up Placebo/ PEG/RBV PEG/RBV PEG/RBV Post-Therapy Follow-Up Weeks Response Guided Therapy: if HCV RNA <25 IU/mL at Week 4 and undetectable at Week 12, complete treatment at Week 24 QUEST 1 and QUEST 2: GT 1, Treatment Naïve PROMISE: GT 1, Prior Relapsers *PEG/RBV=Peginterferon/Ribavirin

16 SVR12 Rates in Treatment Naive Patients (QUEST 1 and QUEST 2 Combined) 419/ / / / / / 83 49/ 84 23/ / / 133 *Observed prevalence of Q80K variants at baseline in US population in the Phase 2b/3 trials: 48% of GT 1a and 0% of GT 1b patients Simeprevir (OLYSIO ) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

17 Mean values (µmol/l) Mean values (µmol/l) Simeprevir is Well Tolerated Bilirubin Hemoglobin SMV/PR Placebo/PR SMV/PR Placebo/PR Weeks Weeks Mild unconjugated hyperbilirubinemia transporter No anemia signal beyond PEG/RBV Rash up to 25% (mild) Manns M, et al. EASL Abst

18 Adverse Reactions (All Grades): 3% Higher Frequency Among Subjects Receiving SMV/PEG/RBV vs Placebo/PEG/RBV* Preferred Term or Grouped Term SMV/PEG/RBV (First 12 Weeks) N=781 Placebo/PEG/RBV (First 12 Weeks) N=397 Rash (including photosensitivity)** 28% 20% Pruritus 22% 15% Nausea 22% 18% Myalgia 16% 13% Dyspnea 12% 8% *During the first 12 weeks of treatment (pooled phase 3 trials) **Grouped term rash includes 26 preferred terms Simeprevir (OLYSIO ) Prescribing Information. Janssen Therapeutics, Titusville, NJ. November, 2013.

19 Other Important Points SMV + PEG/RBV approved regimen for GT 1 patients; however, Q80K polymorphism testing of GT 1a patients is strongly recommended SMV primarily metabolized by the liver In a Phase 1 study, higher SMV concentrations observed in patients with severe hepatic impairment No SMV dose recommendations given in label

20 Sofosbuvir/PEG/RBV Approved Regimen for GT 1

21 Sofosbuvir (SOF) (GS-7977) FDA approval: December 6, 2013 Nucleotide analog NS5B polymerase inhibitor One oral 400 mg tablet once daily with or without food Approved for GT 1, 2, 3 and 4 Sofosbuvir (SOVALDI ) Prescribing Information. Gilead Sciences, Inc. December, 2013.

22 SVR12 Rates in Treatment-Naïve GT 1 and GT 4 Patients (NEUTRINO) 295/ / / 66 27/ 28 Sofosbuvir (SOVALDI ) Prescribing Information. Gilead Sciences, Inc. December, 2013.

23 SVR Rates in Selected Subgroups (NEUTRINO) 252/ / 54 No Cirrhosis Cirrhosis 47/ / 273 Black Non- Black 37/ 52 *Patients with GT 1, METAVIR F3/F4, IL28B non-cc, HCV RNA >800,000 IU/mL (factors traditionally associated with a lower response to interferonbased treatment). Sofosbuvir (SOVALDI ) Prescribing Information. Gilead Sciences, Inc. December, 2013.

24 SVR12 (%) SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors Retrospective multivariate analysis of Phase 2 and 3 SOF data identified 6 negative predictors associated with relapse Prior treatment failure, cirrhosis, IL28B non-cc, HCV RNA 800,000 IU/mL, body weight 75kg, male gender GT 1 GT 2 GT Foster G, EASL, 2014, O / 4 5/ 5 26/ 26 22/ 22 22/ 22 69/ 69 69/ 70 43/ / 78/ 55/ / 65/ 57/ / 18 26/ 33 Number of Negative Predictors 23/ / 6 8/ 15

25 Predictors of Relapse in GT 1 Patients Univariate Factor Odds Ratio p-value Black race Hispanic ethnicity Male Age 50 y Weight 75 kg IL28B non-cc Cirrhosis HCV RNA 800,000 IU/mL Baseline ALT >1.5 x ULN GT 1b Multivariate Factor Odds Ratio p-value Weight 75 kg IL28B non-cc Cirrhosis Foster G, EASL, 2014, O66

26 SOF+RBV: Treatment-Emergent Adverse Events Reported in >5% of Subjects in Any Treatment Arm Adverse Event PBO (12 weeks) N=71 SOF+RBV (12 weeks) N=650 SOF+RBV (24 weeks) N=250 Fatigue 24% 38% 30% Headache 20% 24% 30% Nausea 18% 22% 13% Insomnia 4% 15% 16% Pruritus 8% 11% 27% Anemia 0% 10% 6% Irritability 1% 10% 10% Diarrhea 6% 9% 12% Rash 8% 8% 9% Asthenia 3% 6% 21% Myalgia 0% 6% 9% Decreased Appetite 10% 6% 6% Influenza Like Illness 3% 3% 6% SOF/PEG/RBV safety similar to PEG/RBV safety Sofosbuvir (SOVALDI ) Prescribing Information. Gilead Sciences, Inc. December, 2013.

27 Other Important Points SOF metabolized by the kidney Renal impairment No dose adjustment is required for patients with mild to moderate renal impairment Safety and efficacy has not been established in patients with severe renal impairment or end stage renal disease No SOF dose adjustment is recommended for patients with mild, moderate and severe hepatic impairment

28 Simeprevir + Sofosbuvir + RBV Investigational Regimen for GT 1 (Included in AASLD/IDSA guidance document)

29 COSMOS Study Design: Randomised, Multicentre, Open-label Trial Week Arm 1 SMV + SOF + RBV Post-treatment follow-up Randomised 2:1:2:1 Arm 2 Arm 3 SMV + SOF + RBV SMV + SOF Post-treatment follow-up Post-treatment follow-up Arm 4 SMV + SOF Post-treatment follow-up SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day (BID) Cohort 1: METAVIR F0-F2, prior null responders Cohort 2: METAVIR F3-F4, prior null responders or treatment-naïve Stratified by treatment history, HCV GT 1a/1b BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment Lawitz, E. et al. EASL 2014, Abstract #O165

30 Proportion of patients (%) SVR12 in Cohort 2 (F3/F4 Treatment Naïve and Prior Nulls) SVR12 Non-VF Relapse 3% 2/30 2/27 1/14 3/87 2% 2/87 93% 100% 93% 93% 94% 28/30 16/16 25/27 13/14 82/87 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF SMV/SOF±RBV 24 weeks 12 weeks Overall Is there a need for RBV? Non-VF, Non-virologic failure: patients who did not achieve SVR12 for reasons other than virologic failure Lawitz, E. et al. EASL 2014, Abstract #O165

31 SMV + SOF ± RBV: Adverse Events Patients, n (%) SMV/SOF + RBV (N=30) 24 weeks 12 weeks SMV/SOF (N=16) SMV/SOF + RBV (N=27) SMV/SOF (N=14) Total (N=87) Fatigue 15 (50.0) 6 (37.5) 9 (33.3) 3 (21.4) 33 (37.9) Headache 7 (23.3) 3 (18.8) 5 (18.5) 2 (14.3) 17 (19.5) Nausea 6 (20.0) 3 (18.8) 4 (14.8) 2 (14.3) 15 (17.2) Anemia 7 (23.3) 1 (6.3) 3 (11.1) 0 11 (12.6) Pruritus 5 (16.7) 1 (6.3) 3 (11.1) 2 (14.3) 11 (12.6) Dizziness 4 (13.3) 3 (18.8) 3 (11.1) 1 (7.1) 11 (12.6) Rash 4 (13.3) 0 5 (18.5) 1 (7.1) 10 (11.5) Photosensitivity / sunburn* 2 (6.7) 1 (6.3) 1 (3.7) 1 (7.1) 5 (5.7) *No sun-protective measures were in place for this trial Lawitz, E. et al. EASL 2014, Abstract #O165

32 What Does The Guidance Recommend For Treatment Naïve GT 1 Patients?

33 Guidance Document Language This section assumes that a decision to treat has been made and provides guidance regarding optimal treatment. In many instances, however, it may be advisable to delay treatment for some patients with documented early fibrosis stage (F0-F2), because waiting for future highly effective, pangenotypic, DAA combinations in IFN-free regimens may be prudent. AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

34 Recommended Regimens: GT 1 Treatment Naïve Patients Eligible To Receive IFN SOF + PEG/RBV for 12 weeks Not Eligible To Receive IFN SOF + SMV ± RBV for 12 weeks (not FDA approved) Should be considered ONLY in those patients who require immediate treatment AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

35 Alternative Regimens: GT 1 Treatment Naïve Patients Eligible To Receive IFN SMV + PEG/RBV for 12 weeks followed by PEG/RBV for an additional 12 weeks Only in GT 1b patients GT 1a patients in whom Q80K polymorphism is not detected prior to treatment AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

36 Alternative Regimens: GT 1 Treatment Naïve Patients Not Eligible To Receive IFN SOF + RBV for 24 weeks Preliminary data suggest that this regimen may be less effective than daily SOF plus SMV, particularly among patients with cirrhosis Should be considered ONLY in those patients who require immediate treatment AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

37 Regimens Not Recommended: GT 1 Treatment Naïve Patients PEG/RBV with or without telaprevir or boceprevir for 24 to 48 weeks Monotherapy with PEG, RBV or a DAA AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

38 What About Prior Nonresponders?

39 Case 2

40 Patient History (June 2014) 57 year old Caucasian female CHC diagnosed in 2003 Treated with PEG/RBV in 2004 Non SVR (null responder; <2 log decline in HCV RNA after 12 weeks of therapy) Treated with telaprevir + PEG/RBV in 2012 Non SVR (RVR with breakthrough infection after 7 weeks on therapy)

41 Disease Characteristics/Labs (June 2014) Genotype IL28B METAVIR (biopsy) BL viral load 1a CT F3 2,300,000 IU/mL Hemoglobin 12.6 g/dl Neutrophils 1,300 cells/mm 3 Platelets 150,000 cells/mm 3 ALT 96 IU/L

42 Discussion How would you manage this patient today? Do you require additional information? If so, what? What are the most important factors influencing your decision?

43 What Does The Guidance Document Recommend For GT 1 Previous Nonresponders?

44 Recommended Regimen: GT 1 Previous Nonresponder Patients Previously failed PEG/RBV SOF + SMV ± RBV for 12 weeks Previously failed PEG/RBV + Protease Inhibitor SOF + PEG/RBV for 12 weeks followed by PEG/RBV for up to an additional 12 weeks AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

45 Alternative Regimen: GT 1 Previous PEG/RBV (With or Without Protease Inhibitor) Nonresponder Patients Eligible to Receive IFN SOF + PEG/RBV for 12 weeks followed by PEG/RBV for up to an additional 12 weeks Ineligible to Receive IFN SOF + RBV for 24 weeks AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

46 Alternative Regimen: GT 1 Previous PEG/RBV (Without Protease Inhibitor) Nonresponder Patients Eligible to Receive IFN SMV + PEG/RBV for 12 weeks followed by PEG/RBV for an additional 36 weeks (48 week total duration) AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

47 Regimens Not Recommended: GT 1 Prior Nonresponder Patients PEG/RBV with or without telaprevir or boceprevir Monotherapy with PEG, RBV or a DAA AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 13, 2014.

48 Have All Limitations of Boceprevir and Telaprevir Based Therapies Been Addressed By Recently Approved Regimens?

49 Have The Limitations of First Generation DAAs Been Addressed? Interferon and ribavirin backbone required GT 1 and GT 4: PEG/RBV still required GT 2 and GT 3: Interferon-free (SOF+RBV) Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir SOF and SMV both once daily dosing Response guided therapy (RGT) (both) and lead-in (boceprevir) complicated SOF and SMV regimens do not require RGT or lead-in

50 Have The Limitations of First Generation DAAs Been Addressed? Treatment Duration: week treatment GT 1: SOF+PEG/RBV for 12 weeks GT 1: SMV + SOF for 12 weeks GT 1: SMV+PEG/RBV for weeks GT 2: SOF+RBV for 12 weeks GT 3: SOF+RBV for 24 weeks GT 4: SOF+PEG/RBV for 12 weeks

51 Have The Limitations of First Generation DAAs Been Addressed? Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans) GT 1: SMV+PEG/RBV and SOF+PEG/RBV demonstrate improved efficacy in difficult to cure populations GT 2: SOF+RBV strong efficacy GT 3: SOF+RBV less efficacious in null responders with cirrhosis

52 Have The Limitations of First Generation DAAs Been Addressed? Hematologic (both) and rash/dermatological (telaprevir) adverse events No hematologic signal with SMV or SOF monotherapy GT 1: SMV and SOF both require PEG/RBV backbone and hematologic adverse events comparable to PEG/RBV control arm GT 2 and 3: Interferon free regimens have no hematologic signal beyond anemia associated with RBV Drug-drug interactions SMV has DDIs with many of the same drug classes as boceprevir and telaprevir SOF does not have any significant drug:drug interactions

53 General Discussion Q & A

54 A 45-day Follow-up Survey will be sent to your address. Thank you for completing the survey.

55 For more information on the Chronic Liver Disease Foundation (CLDF) and the International Coalition of Hepatology Providers (IC-HEP) please visit Thank You Abbvie and Bristol-Myers Squibb for supporting this program

56

57 Session 2

58 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 joint-sponsorship of the Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease Foundation. The Annenberg Center for Health Sciences at Eisenhower is accredited by the ACCME to provide continuing medical education for physicians. The Annenberg Center for Health Sciences at Eisenhower designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credits commensurate with the extent of their participation in the activity. Annenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. A maximum of 1.5 contact hours may be earned for successful completion of this activity. Provider is approved by the California Board of Registered Nursing, Provider #13664, for 1.5 contact hours.

59 Learning Objectives Recognize the clinical trial data, AASLD treatment guidelines and approved product labeling for available therapies. Identify patients who are good candidates for currently available therapy versus those patients that would benefit more from future therapies. Use the knowledge gained to maximize clinical outcomes on a case-by-case basis.

60 Global Distribution and Prevalence of HCV Genotypes: US Focus on GT 1 North America, High income 3 (Other) 4 6 1a 2 (Other) 1b Messina JP et al, Hepatology, July 2014, epub

61 HCV: Update on Interferon-Free Therapies GT 1 Patients

62 Multitargeted Approach for Treatment: Protease Inhibitors, Polymerase Inhibitors and NS5A Inhibitors 5 UTR region 9.6 kb RNA 3 UTR region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Polyprotein Processing C E1 E2 Core Envelope Glycoproteins p7 NS2 Protease NS3 NS4A Serine Helicase Serine Protease Protease Cofactor NS4B NS5A Ledipasvir NS5B RNA-dependent RNA polymerase Simeprevir **MORE COMING SOON NS3-4A protease inhibitors Sofosbuvir nucleoside analogs NS5B polymerase inhibitors non- nucleoside analogs McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48: **COMING SOON

63 Ledipasvir (NS5A inhibitor) + sofosbuvir (nucleotide polymerase inhibitor) + RBV GT 1 Treatment-naïve and Treatment-experienced

64 LDV/SOF Regimen in GT 1 Program ION-1 Treatment naïve patients 12 vs 24 weeks; + RBV 15.7% (136/865) with cirrhosis ION-3 Treatment-naïve patients 8 vs 12 weeks; + RBV in 8 week arms Excluded patients with cirrhosis ION-2 Treatment-experienced patients 12 vs 24 weeks; + RBV 20% (88/440) with cirrhosis

65 LDV/SOF + RBV for 12 vs 24 Weeks in Treatment-naïve Patients: Study Design (ION-1) Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF SVR12 LDV/SOF + RBV SVR12 LDV/SOF SVR12 LDV/SOF + RBV SVR12 GT 1 HCV treatment-naïve patients 15.7% cirrhotics Platelet count >50,000 and no neutrophil minimum Stratified by HCV subtype (1a or 1b) and cirrhosis Afdhal et al. N Eng J Med 2014;370:

66 SVR12 (%) SVR12 (%) LDV/SOF + RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-naïve Patients (ION-1) Non-cirrhotic Cirrhotic 179/ / / / / 33 33/ 33 31/ 32 36/ 36 LDV/S OF LDV/SOF + RBV LDV/S OF LDV/SOF + RBV 12 Weeks 24 Weeks Afdhal et al. N Eng J Med 2014;370: LDV/S OF LDV/SOF + RBV LDV/S OF LDV/SOF + RBV 12 Weeks 24 Weeks

67 LDV/SOF + RBV for 8 vs 12 Weeks in Treatmentnaive Patients: Study Design (ION-3) Wk 0 Wk 8 Wk 12 Wk 20 Wk 24 LDV/SOF SVR12 LDV/SOF + RBV SVR12 LDV/SOF SVR12 GT 1 treatment-naïve patients without cirrhosis 647 patients randomized 1:1:1 across three arms Stratified by HCV subtype (1a or 1b) Kowdley KV et al. N Eng J Med 2014; 370:

68 SVR12 (%) LDV/SOF + RBV for 8 vs 12 Weeks: SVR12 in GT 1 Treatment-naïve Non-cirrhotic Patients (ION-3) p= / / /216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 Weeks 12 Weeks Error bars represent 95% confidence intervals. Kowdley KV et al. N Eng J Med 2014; 370:

69 GT 1 Treatment Naïve Non-Cirrhotics: Baseline Viral Load Defines Treatment Duration LDV/SOF 8 Weeks (N=215) LDV/SOF 12 Weeks (N=216) SVR12 94% (202/215) 96% (208/216) Relapse Rates Overall <6 M IU/mL >6 M IU/mL 5% (11/215) 2% (2/123) 10% (9/92) 1% (3/216) 2% (2/131) 1% (1/85) 8 week LDV/SOF regimen should only be considered in GT 1, treatment-naïve, non-cirrhotic patients with BL viral load <6 million IU/mL Ledipasvir/sofosbuvir (HARVONI ) Prescribing Information. Gilead Sciences, Foster City, CA. October, 2014 (Adapted from Table 6).

70 Normalized PRO change, % LDV/SOF ± RBV: Patient Reported Outcomes (PRO) in Treatment-Naïve GT 1 Patients Changes in PROs after 12 Weeks of Treatment 8.0% LDV/SOF+RBV LDV/SOF 6.0% 4.0% 2.0% 0.0% -2.0% -4.0% * -6.0% -8.0% -10.0% Physical P= SF-36 Mental P= Fatigue P< FACIT-F Total P= CLDQ-HCV P= * Work Productivity P= Activity Impair-ment P= Younossi Z, EASL, 2014, P1324 *Significant (P<0.05) decrement from patients own baseline Significant (P<0.05) improvement from patients own baseline Note: the PROs are normalized to the 0-100% scale using their original ranges

71 LDV/SOF + RBV for 12 vs 24 Weeks in Treatmentexperienced Patients: Study Design (ION-2) Wk 0 Wk 12 Wk 24 Wk 36 LDV/SOF LDV/SOF + RBV SVR12 SVR12 LDV/SOF LDV/SOF + RBV SVR12 SVR12 GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor 20% enrollment of patients with cirrhosis No upper age or BMI limit Platelet count 50,000/mm 3, no neutrophil minimum 440 patients randomized 1:1:1:1 across four arms Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response Afdhal et al. N Engl J Med 2014;370:

72 SVR12 (%) LDV/SOF + RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-experienced Cirrhotic Patients (ION-2) PI+PEG/RBV Failure PEG/RBV Failure 12/14 7/8 11/13 7/9 14/14 8/8 13/13 9/9 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Afdhal et al. N Engl J Med 2014;370:

73 LDV/SOF: Relapse Rates in GT 1 Treatment-Experienced Cirrhotics Relapse Rate in Patients Without Cirrhosis Relapse Rate in Patients With Cirrhosis LDV/SOF 12 Weeks (N=108) LDV/SOF 24 Weeks (N=109) 5% (4/86) 0% (0/86) 14% (3/22) 0% (0/22) GT 1 patients who failed prior therapy and have cirrhosis should be treated for 24 weeks with LDV/SOF. Ledipasvir/sofosbuvir (HARVONI ) Prescribing Information. Gilead Sciences, Foster City, CA. October, 2014 (Adapted from Table 12).

74 Paritaprevir/r (protease inhibitor/ritonavir) + ombitasvir (NS5A inhibitor) + dasabuvir (non-nucleoside polymerase inhibitor) + RBV (3D + RBV) GT 1 Treatment-naïve and Treatment-experienced

75 3D + RBV Regimen in GT 1 Program SAPPHIRE-I Treatment naïve non-cirrhotic patients 12 week treatment + RBV PEARL-III GT 1a treatment-naïve non-cirrhotic patients 12 week treatment + RBV PEARL-IV GT 1b treatment-naïve non-cirrhotic patients 12 week treatment + RBV SAPPHIRE-II Treatment-experienced non-cirrhotic patients 12 week treatment + RBV TURQUOISE-II Treatment-naïve and treatment-experienced cirrhotic patients 12 vs 24 week treatment + RBV

76 3D + RBV for 12 Weeks in Treatment-Naive GT 1 Patients: Study Design (SAPPHIRE-I) Double-blind Treatment Period Open-label Treatment Period 3D + RBV Placebo 3D + RBV Genotype 1 Treatment-naïve No cirrhosis Primary analysis: SVR12 Weeks 3D: Co-formulated ABT-450/ritonavir/ombitasvir, 150 mg/ 100 mg/ 25 mg + dasabuvir, 250 mg RBV: mg daily, weight-based Feld JJ, et al. N Eng J Med 2014; 370:

77 SVR12 (%) 3D + RBV for 12 Weeks : SVR12 in Treatmentnaïve Non-cirrhotic Patients (SAPPHIRE-I) / / /151 Feld JJ, et al. N Eng J Med 2014; 370: All Patients GT1a GT1b

78 SVR12 (%) 3D + RBV for 12 Weeks: SVR12 by Treatment-naïve Non-cirrhotic Patients by Subgroup (SAPPHIRE-I) Male Female Black Non- Black <30 >30 F0-F1 F2 F3 <800K >800K Yes No Gender Race BMI Fibrosis Baseline RBV (kg/m 2 ) Stage HCV RNA Modification (IU/mL) Feld JJ, et al. N Eng J Med 2014; 370:

79 SVR12 (%) 3D + RBV for 12 Weeks: SVR12 in GT1a and GT1b Treatment-naïve Non-cirrhotic Patients (PEARL-III and PEARL-IV) GT 1a GT 1b 97/ / / /209 3D Regimen + RBV 3D Regimen 3D Regimen + RBV 3D Regimen Ferenci P et al. N Engl J Med 2014;370:

80 3D + RBV in Treatment-experienced GT 1 Non-cirrhotic Patients: Study Design (SAPPHIRE-II) Double-blind Treatment Period 3D + RBV Open-label Treatment Period Placebo 3D + RBV Weeks Genotype 1 Prior PR (Relapse, Partial response, or Null response) No cirrhosis Primary analysis: SVR12 Zeuzem S, et al. N Engl J Med 2014;370:

81 SVR12 (%) 3D + RBV for 12 Weeks: SVR12 in Treatmentexperienced Non-cirrhotic Patients (SAPPHIRE-II) / / /123 All Patients GT1a GT1b Zeuzem S, et al. N Engl J Med 2014;370:

82 SVR12 (%) 3D + RBV for 12 Weeks: SVR12 in Treatmentexperienced Non-cirrhotic Patients (SAPPHIRE-II) /86 65/65 139/146 Zeuzem S, et al. N Engl J Med 2014;370: Prior Relapse Prior Partial Response Prior Null Response

83 3D + RBV in Treatment-naïve and Treatmentexperienced GT 1 Cirrhotic Patients: Study Design (TURQUOISE-II) 3D + RBV (N=208) SVR12 3D + RBV (N=172) SVR12 Day 0 Week 12 Week 24 Compensated cirrhosis (Child-Pugh score <6) Poordad F, et al. N Engl J Med. 2014;370:

84 TURQUOISE II: ABT-450/r-Ombitasvir + Dasabuvir ± RBV P= Relapse/viral breakthrough in 6% (12 wks) and 2% (24 wks) Poordad F et al. N Engl J Med; 2014;370:

85 SVR12 (%) 3D + RBV for 12 vs 24 Weeks: SVR12 in GT 1a Cirrhotic Patients by Prior Treatment Response to PEG/RBV (TURQUOISE-II) 12 weeks 24 weeks /76 62/65 40/50 39/42 11/11 10/10 14/15 13/13 All Treatment- Experienced Prior Null Responder Prior Partial Responder Prior Relapser Poordad F, et al. N Engl J Med. 2014;370:

86 SVR12 (%) 3D + RBV for 12 vs 24 Weeks: SVR12 in GT 1b Cirrhotic Patients by Prior Treatment Response to PEG/RBV (TURQUOISE-II) 12 weeks 24 weeks /46 33/33 25/25 20/20 6/7 3/3 14/14 10/10 All Treatment- Experienced Prior Null Responder Prior Partial Responder Prior Relapser Poordad F, et al. N Engl J Med. 2014;370:

87 3D Regimen + RBV: Relapse Rates in GT 1 Cirrhotics 3D Regimen + RBV 12 Weeks 3D Regimen + RBV 24 Weeks Relapse Rate in All Patients With Cirrhosis 5.9% (12/203)* 0.6% (1/164) *7/12 (58.3%) relapsers had GT 1a infection and prior null response to PEG/RBV 3D regimen + RBV undergoing FDA review; therefore, approved duration for cirrhotics has not been defined. Poordad F, et al. N Engl J Med. 2014;370:

88 3D + RBV: 12 Week Treatment Duration and Absence of Interferon Minimizes Effect on Hemoglobin (Non-cirrhotic Patients) SAPPHIRE-I 3D + RBV Treatment-naive Patients SAPPHIRE-II 3D + RBV Treatmentexperienced Patients SAPPHIRE-I and SAPPHIRE-II 3D + RBV Treatment-naive and Treatment-experienced Patients N = 473 N = 297 N = 770 Post-baseline Hemoglobin, n/n (%) Grade 1 (<LLN-10.0 g/dl) Grade 2 (< g/dl) Grade 3 (< g/dl) Grade 4 (<6.5 g/dl) 223/469 (47.5) 27/469 (5.8) /296 (52.0) 14/296 (4.7) 1/296 (0.3) /765 (49.3) 41/765 (5.4) 1/765 (0.1) 0 All anemia events, n (%) 30 (6.3) 29 (9.8) 59 (7.7) Discontinuation due to anemia events, n Sulkowski et al., IAS Conference, July 2014

89 Daclatasvir (NS5A inhibitor) + asunaprevir (protease inhibitor) GT 1b only Treatment-naïve and Treatment-experienced

90 Randomization 2:1 Daclatasvir + Asunaprevir for 24 Weeks in GT 1b Patients (HALLMARK-DUAL) NDA Withdrawn October 7 th, 2014 Day 1 Week 12 Week 24 Week 48 DCV + ASV Follow up 24 weeks Treatment-naive DCV-PBO + ASV-PBO STOP Enter another study: DCV + ASV 24 weeks Nonresponder DCV + ASV Follow up 24 weeks Ineligible/intolerant DCV + ASV Follow up 24 weeks Patients infected with HCV genotype 1b Treatment-naive Nonresponders: prior null or partial response to PEG/RBV Interferon-ineligible/intolerant (treatment-naive or -experienced) due to Depression Anemia/neutropenia Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia SVR 12 Manns M, et al. Lancet, July 28, 2014, epub (

91 Daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide polymerase inhibitor) + RBV GT 1 Will not be available until FDA approves daclatasvir

92 SVR12 (%) DCV/SOF + RBV for 12 vs 24 Weeks: SVR12 in GT 1 Patients Treatment Naive Prior PI/PEG/RBV Failures /41 39/41 14/14 21/21 15/15 19/20 DCV/SOF DCV/SOF + RBV DCV/SOF DCV/SOF + RBV 12 Weeks 24 Weeks Sulkowski MS et al., N Engl J Med 2014;370:

93 GT 1 Summary

94 Efficacy in GT 1 Treatment-naïve Patients With and Without Cirrhosis (8-12 Week Treatment Regimens) Regimen Duration Patient Population SVR12 Patients SOF + SMV 12 Weeks F3-F4 (COSMOS) 86% 7 SOF + SMV + RBV 12 Weeks F3-F4 (COSMOS) 92% 12 LDV + SOF LDV + SOF + RBV 12 Weeks 8 Weeks 12 Weeks 8 Weeks Non-cirrhotic (ION-1) Non-cirrhotic (ION-3) Cirrhotic (ION-1) Non-cirrhotic (ION-3) Non-cirrhotic (ION-1) Cirrhotic (ION-1) Non-cirrhotic (ION-3) 3D Regimen 12 Weeks GT 1b non-cirrhotic (PEARL- III) 3D Regimen + RBV 12 Weeks Non-cirrhotic (SAPPHIRE-I) GT 1a non-cirrhotic (PEARL- IV) GT 1b non-cirrhotic (PEARL- III) Cirrhotic (TURQUOISE-II) 100% 95% 97% 94% 100% 100% 93% % % 97% 99.5% 94% DCV + SOF 12 Weeks All (15% cirrhotic) 98% 41 DCV + SOF + RBV 12 Weeks All (12% cirrhotic) 95%

95 Efficacy in GT 1 Treatment-experienced Patients With and Without Cirrhosis (12 Week Treatment Regimens) Regimen Duration Patient Population SVR12 Patients SOF + SMV 12 Weeks F0-F2 Null (COSMOS) F3-F4 (COSMOS) SOF + SMV + RBV 12 Weeks F0-F2 Null (COSMOS) F3-F4 Null (COSMOS) LDV + SOF 12 Weeks Non-cirrhotic (ION-2) Cirrhotic (ION-2) LDV + SOF + RBV 12 Weeks Non-cirrhotic (ION-2) Cirrhotic (ION-2) 3D Regimen + RBV 12 Weeks Non-cirrhotic (SAPPHIRE-II) Prior relapse Prior partial response Prior null response Cirrhotic (TURQUOISE-II) Prior relapse Prior partial response Prior null response 93% 100% 96% 93% 95% 86% 100% 82% 95% 100% 95% 97% 94% 87%

96 Efficacy in GT 1 Treatment-experienced Patients With and Without Cirrhosis (24 Week Treatment Regimens) Regimen Duration Patient Population LDV + SOF 24 Weeks Non-cirrhotic (ION-2) Cirrhotic (ION-2) LDV + SOF + RBV 24 Weeks Non-cirrhotic (ION-2) Cirrhotic (ION-2) 3D Regimen + RBV 24 Weeks Cirrhotic (TURQUOISE-II) Prior relapse Prior partial response Prior null response SVR12 99% 100% 99% 100% 100% 100% 95% DCV + SOF 24 Weeks All (14% cirrhotic) 100% 21 DCV + SOF + RBV 24 Weeks All (30% cirrhotic) 95% 20 Patients

97 Considerations for Safety Monitoring During HCV Treatment Maximize adherence via pretreatment education DAA + PEG/RBV Safety profile similar to PEG/RBV Continue to monitor for cytopenias, depression, etc DAA(s) + RBV Favorable safety profile Monitoring for anemia still important All DAA regimen (no PEG/RBV) Favorable safety profile Individualized follow up as deemed necessary

98 Case Discussion

99 Case A 53 year old Caucasian male, diagnosed with chronic hepatitis C in 2009 Past medical history IV drug use in college Social alcoholic drinks/week Owns construction company Work productivity drastically reduced due to debilitating fatigue

100 Case Hemoglobin 15.6 g/dl Neutrophils 1,000 cells/mm 3 Platelets 195,000 cells/mm 3 AST; ALT 100 IU/L; 73 IU/L Albumin 3.8 g/dl Bilirubin 0.6 mg/dl Subtype GT 1b IL28B CT BL viral load 2.2 million IU/mL

101 Case Additional tests needed? Disease severity Abdominal imaging Noninvasive blood tests Transient elastography Liver biopsy

102 Case Liver biopsy performed METAVIR F2 Are any additional tests necessary? Would you start treatment for HCV? If so, with what? For how long? Would you use ribavirin?

103 When and in Whom to Initiate HCV Therapy Treatment is recommended for patients with chronic HCV infection (Class I, Level A) 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 extrahepatic hepatitis C complications are given high priority. AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed August 28, 2014.

104 Case High Priority for Treatment Owing to High Risk for Complications Fibrosis (Metavir F2) HIV-1 coinfection HBV coinfection Other coexistent liver disease (eg, NASH) Debilitating fatigue Type 2 Diabetes mellitus (insulin resistant) Porphyria cutanea tarda AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed August 28, 2014.

105 Conclusions

106 Have The Following Limitations of First Generation DAAs Been Addressed? Interferon and ribavirin backbone required? Twice per day dosing (BID) for telaprevir and three times per day (TID) dosing for boceprevir? Response guided therapy (both) and lead-in (boceprevir)? week treatment duration? Limited efficacy in difficult-to-cure populations (e.g., patients with cirrhosis, prior null responders, African-Americans)? Hematologic (both) and rash/dermatological (telaprevir) adverse events? Drug:drug interactions?

107 Overall Conclusions New regimens >95% SVR for treatment-naïve patients Duration <12 weeks Cirrhotics: some require 24 weeks? Interferon free Ribavirin not required for some regimens Favorable safety profile Continue to follow for AASLD/IDSA recommendations Access and insurance coverage will likely remain a challenge for many patients

108 General Discussion Q & A

109 A 45-day Follow-up Survey will be sent to your address. Thank you for completing the survey.

110 For more information on the Chronic Liver Disease Foundation (CLDF) and the International Coalition of Hepatology Providers (IC-HEP) please visit Thank You AbbVie and Bristol-Myers Squibb for supporting this program

111 Join the Hepatitis C Link to Care Physician Resource Directory One of the main focuses of the CLDF is HCV screening and liking patients who tested positive to health care professionals In order for large screening efforts to be successful, linkage between practices actively screening must be linked to centers familiar with HCV treatment and patient follow up. YOUR ROLE: By opting in to our Physician Resource Directory, your name will be posted on our website ( which implies that you are interested in treating HCV patients and are currently accepting new HCV patient referrals TO OPT IN: Please complete the form located in your meeting folder and return to a staff member before the end of the meeting.