1. CADTH SYMPOSIUM : HCV: NATURAL HISTORY AND THERAPEUTICS Alnoor Ramji Gastroenterology & Hepatology Clinical Associate Professor Division of Gastroenterology University Of British Columbia St. Paul’s Hospital Site ramji_a@hotmail.com

2. Company NameRelationship AbbvieInvestigator, consultant BIInvestigator, Consultant BMSInvestigator, Consultant, Speaker Gilead Sci. IncInvestigator, Consultant, Speaker Hoffman LaRoche Investigator, Consultant, Speaker Nursing Support Janssen (J. & J.)Investigator, Consultant, Speaker NovartisInvestigator Merck & Co. Investigator, Consultant, Speaker Nursing Support Vertex PharmaceuticalsInvestigator, Consultant, Speaker Disclosures

3. Objectives Review the natural history of hepatitis C and its complications. Understand Treatment options for hepatitis C – Pegylated-interferon + ribavirin +/- Direct acting anti-virals (DAA’s). – Combination DAA’s

4. 1a, 1b 2a, 2b, 3a 1a, 1b 2a, 2b, 2c, 3a 4 5a 1b 1b, 6 1b, 3a 3b 4 Fang et al. Clin Liver Dis. 1997. HCV Infection: Worldwide Genotype Distribution 1a, 1b, 2b, 3a 2a

5. 5 HCC: hepatocellular carcinoma. 1. Alter and Seeff. Semin Liver Dis. 2000;20:17-35; 2. Pinette et al. Public Health Agency of Canada. Available from: http://www.phac-aspc.gc.ca/hepc/pubs/pdf/hepc_guide eng.pdf; 3.Myers et al. Can Gastroenterol. 2012;26:359-75. Projection of Lifetime Outcomes 1 100 patients with acute HCV infections 24 patients chronic, nonprogressive 24 patients chronic, nonprogressive 24 patients severe progressive hepatitis 24 patients severe progressive hepatitis 32 patients variable progression 32 patients variable progression 20 patients recover 80 patients persistent infection 80 patients persistent infection All patients should seek antiviral therapy 2,3 End-stage disease, HCC, liver transplantation, death End-stage disease, HCC, liver transplantation, death Treatment failure Sustained response/cure Outcomes:

6. Disease Progression and Morbidities 6 Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie 1. O’Leary 2008; 2. Perz 2006; 3. White 2008 Disease progression in patients with chronic HCV Morbidities associated with chronic HCV infection 1,2 Cirrhosis Decompensated cirrhosis: Ascites, varices, Encephalopathy Hepatocellular carcinoma (HCC)

7. 312 patients with initially compensated cirrhosis of viral aetiology Cirrhotic patients at risk of serious morbidity Benvegnù L, et al. Gut 2013; 53: 744‒9 Patients at risk HCC31231131030329726822618915312994654527115 Variceal bleeding312 30930126923719016313197714429137 Ascites31231131230529625922318115212593604830159 Encephalopathy312 30930027023519216112795654330137 Cumulative risk (%) Years of follow-up HCC Variceal bleeding Ascites Portal-systemic encephalopathy 50 40 30 20 10 0 0123456789 1112131415

8. Variceal Hemorhage

9. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. SVR (%) IFN 6 mos PegIFN/ RBV 12 mos IFN 12 mos IFN/RBV 12 mos PegIFN 12 mos 2001 1998 2011 Standard IFN RBV PegIFN 1991 DAAs PegIFN/ RBV/ DAA IFN/RBV 6 mos 6 16 34 42 39 55 70+ 0 20 40 60 80 100 The Advancing Present 2014/5 90-98 PegIFN/ RBV/ DAA Or DAA+RBV

10. Viral Eradication Improves All-Cause Mortality 10 References: 1. Ravazi 2012; 2. Burra 2009; 3. Guillouche 2011; 4. Van der Meer 2012 Cure = SVR = reduced risk of — All-cause mortality; Liver-related mortality; HCV-related complications:- Progression to HCC or liver failure 4 Patient survival outcomes with and without SVR Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie

11. HCV Lifecycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors *Role in HCV lifecycle not well defined NS5A* inhibitors

12. 0 20 40 60 80 100 SVR (%) PegIFN/RBV BOC or TVR + PegIFN/RBV 38-44 67-81 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2012 – 2014: SVR Rates: Boceprevir or Telaprevir with PEG-INF + Ribavirin in Genotype 1 Treatment-Naive Patients: upto 48 Weeks F0-2F3-4 52-62

13. Boceprevir Triple therapy Safety Profile 48 PR n=363 BOC RGT n=368 BOC/PR48 n=366 Median treatment duration, days203197335 DeathsN=4N=1 Serious AEs9%11%12% Discontinued due to AEs16%12%16% Dose modification due to AEs26%40%35% Hematologic parameters Neutrophil count (<750 to 500/mm 3 / <500/mm 3 ) 14% / 4%24% / 6%25% / 8% Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL) Discontinuation due to anemia Dose reductions due to anemia Erythropoietin use Mean (median) days of use 26% / 4% 1% 13% 24% 121 (109) 45% / 5% 2% 20% 43% 94 (85) 41% / 9% 2% 21% 43% 156 (149)

14. Adverse EventArm 1 (PR48); n=363 (%)Arm 2 (RGT); n=368 (%)Arm 3 (BOC/PR48); n=366 (%) Fatigue595257 Headache424543 Nausea404642 Anemia2949 Dysgeusia183743 Chills283633 Pyrexia323330 Insomnia323132 Alopecia272028 Decreased Appetite252624 Pruritis262325 Neutropenia2125 Influenza Like Illness252322 Myalgia262124 Rash222423 Irritability2422 Depression212319 Diarrhea19 23 Dry Skin18 22 Dyspnea161822 Dizziness152117 Boceprevir Triple: Common Treatment-Related Adverse Events* *Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

15. 0 20 40 60 80 100 SVR (%) Simeprevir 85% 90% 2014 /2015 :Virologic Response to PEG-INF + RBV + Simeprevir or Sofosbuvir in Genotype 1 Treatment-Naive Patients 80% CirrhosisNo Cirrhosis 60% Sofosbuvir CirrhosisNo Cirrhosis Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission. Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.

16. 0 20 40 60 80 100 SVR (%) SOF/ LDV +/- RBV x 8-12 wks 97-100% 93-100% Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 Poordad F, et al. EASL 2014. Abstract O163 2015 /2016 :Virologic Response to Non-interferon based therapy: Genotype 1 :Treatment-Naive Patients: Non-cirrhotic and cirrhotic sub-groups ABT 450/rtv + ombitasvir + dasabuvir+RBV X 12 wks

17. 0 20 40 60 80 100 SVR (%) SOF/ LDV +/- RBV 12-24 wks 82-100% 93-100% 2015 /2016 :SVR to Non-interferon based therapy: Geno. 1 :Treatment Experienced Patients: Non-cirrhotic and cirrhotic sub-groups ABT 450/rtv + ombitasvir + dasabuvir+RBV X 12 -24 wks Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print] Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

18. AEs SAPPHIRE ISAPPHIRE II 3 DAA + RBV (n = 473) Placebo (n = 158) 3 DAA + RBV (n = 297) Placebo (n = 97) Any AE, n (%)414 (87.5)116 (73.4)271 (91.2)80 (82.5) AE leading to D/C, n (%)3 (0.6)1 (0.6)3 (1.0)0 Any serious AE, n (%)10 (2.1)06 (2.0)1 (1.0) Grade 3/4 lab events, n/N (%)  ALT4/469 (0.9)7/158 (4.4)5/296 (1.7)3/96 (3.1)  AST3/469 (0.6)3/158 (1.9)3/296 (1.0)1/96 (1.0)  Alkaline phosphatase0000  Creatinine––2/297 (0.7)0  Total bilirubin13/469 (2.8)07/296 (2.4)0  Hemoglobin < 8 g/dL001/296 (0.3)0 Hemoglobin < 10 to 8 g/dL, %5.804.70 Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614. ABT 450/rtv + ombitasvir + dasabuvir+RBV (Holkira) with RBV in Non-cirrhotic GT1 Pts: Tolerance compared to placebo

19. Younossi ZM, AASLD, 2014, Poster #1445 Treatment with LDV/SOF (Harvoni) Improves PROs in CHC Patients with Early as well as Advanced Hepatic Fibrosis

20. 0 20 40 60 80 100 SVR (%) PegIFN/RBV X 24 wks 70-80% 97% Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2014 /2015 :Virologic Response to PEG-INF + RBV vs. Sofosbuvir + RBV (all-oral) in Genotype 2 and 3 Treatment-Naive Patients Geno 2 SOF+RBV X 12 wks 92-94% Geno 3 SOF+RBV X 24 wks Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

21. LDV/SOF (Harvoni) + RBV for HCV Patients with Decompensated Cirrhosis: SVR-12 SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis CTP BCTP C SVR12 (%) 26/3019/2218/2024/27 Error bars represent 90% confidence intervals. LDV/SOF + RBV 12 WeeksLDV/SOF + RBV 24 Weeks SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV Flamm, AASLD, 2014, Oral #239

22. AscitesHepatic Encephalopathy Patients, n SOF + RBV n=25 Observation n=25 SOF + RBV n=25 Observation n=25 Baseline 6952 Week 12 5833 Week 24 0704 Cirrhosis and Portal Hypertension Study (SOF+RBV) Platelets (10 3 /µL) Albumin (g/dL) SOF+RBV Observation 24 weeks ALT (U/L) CTP A CTP B Afdhal N, EASL, 2014, O68 p=0.003 p=NS p=0.001 ‡ SOF+RBV for Treatment of Chronic HCV with Cirrhosis and Portal HTN ± Decompensation: Week 24 Interim Results

23. Hepatitis C: Summary HCV has a slowly progressive course to cirrhosis, with complications of decompensated disease. Newer regimen: all-oral, efficacious, well tolerated Viral eradication / cure in 70-98% Viral eradication has a mortality benefit

24. CADTH SYMPOSIUM : HCV: NATURAL HISTORY AND THERAPEUTICS Alnoor Ramji Gastroenterology & Hepatology Clinical Associate Professor Division of Gastroenterology University Of British Columbia St. Paul’s Hospital Site ramji_a@hotmail.com