Hepatitis C Choices in Care HCV State of the Art Management for a Curable Disease Robert G. Gish MD Robert G Gish Consultants LLC Member VHAC Founding member of CEVHAP Executive Committee (VP): NVHR Senior Medical Director: St Josephs Medical Center Phoenix Professor of Clinical Medicine University of Nevada Las Vegas

Futur e After HEPTIC EMR program Complexity of Hepatitis C Patient Management

Why Treat Chronic Hepatitis C? The disease  Common, chronic, and potentially progressive  Complications are becoming more common Liver failure Hepatocellular carcinoma (HCC)  Decrease transmission  Improve quality of life  Systemic disease  Improve survival due to the linkage of HCV to (non liver) all cause mortality  Decrease immediate and long-term health care costs The treatment  Viral cure, or sustained virologic response (SVR), is achievable  SVR associated with histologic improvement and gradual regression of fibrosis 1  SVR leads to lower risk for liver failure and HCC, and improved survival 2,3 1. Poynard T, et al. Gastroenterology. 2002;122: Craxi A, et al. Clin Liver Dis. 2005;9: Shiratori Y, et al. Ann Intern Med. 2005;142:

Treatment starts NOW with behavior modification Alcohol abstinence Weight loss of OW/Obese No THC use Stop IVDU

HCV as a Systemic Disease Association between chronic HCV infection and:  Diabetes/insulin resistance  Cardiovascular disease  HCV and Brain: decreased cognitive function and QOL  Cancer  Renal impairment Effects of antiviral therapy and SVR on prognosis:  Clear mixed cryoglobulinemia  Decrease liver-related mortality  Abrogate non-liver-related mortality  Stop graft loss in renal and liver transplant patients  Change outcomes in immune suppressed patients with HIV and other treatments or disease states

SVR Reduces Risk of Development of Diabetes in Patients with HCV Veterans Affairs Clinical Case Registry: 27,636 patients with HCV Followed for median 5 years Antiviral treatment initiated Hyder S et al. DDW 2013; poster 608. Hyder S. and et al Digestive Disease week, 2013 HR = 0.77: 95% CI

HCV+ individuals die 15 years sooner Pinchoff J et al. IDWeek 2013; poster 1777.

CHeCS: Annual Rate of Length of Stay (days/year) by FIB4 score*, *FIB4, calculated from ALT, AST, platelet count and patient age, increases with worsening fibrosis; values > 5.88 indicate cirrhosis and end-stage liver disease

HCV-infected persons in CHeCS: Mortality rates also increasing* Year Mortality rate (per 100 py) From: R Mahajan et al, Abstract submitted to IDWeek 2013

The real impact of HCV mortality in the United States* Despite high death rates, only 19% of the 1600 confirmed chronic HCV patients in CHeCS had HCV infection noted on their death certificate; only 30% even of those dying with liver-related conditions 70% had pre-mortem ICD9 codes, liver biopsies, and FIB4 scores indicative of substantial liver damage This suggests that even if all HCV-infected patients are identified before death– clearly, not the case-- actual mortality in them exceeds /yr, most of it contributed to by underlying HCV- related liver disease Whatever the listed cause of disease, HCV-infected persons died 15 years younger than everyone else * Reena Mahajan et al, ‘Rates and Causes of Mortality…”, Manuscript submitted; IDWeek 2013 abstr 1774

Current Treatment

The Evolution of HCV Therapy Strader DB, et al. Hepatology 2004;39: SVR (%) IFN 6 mo IFN/RBV 6 mo PEG-IFN /RBV 12 mo IFN 12 mo IFN/RBV 12 mo PEG-IFN 12 mo PEG-IFN /RBV + PI 6-12 mo % +/- INF RIBA

Side Effects PEG IFN/RBV + new therapies results in increased SVR rates, this may be accompanied by a higher incidence of Anemia, often requiring erythropoietin and/or transfusion Rash Taste abnormalities (dysgeusia) Fatigue Flu-like symptoms Nausea Pruritus/dry skin Neutropenia/thrombocytopenia Fever Depression +++ Poordad F, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2. Telaprevir NDA April 28, Available at:

Patients, n (% patients with at least one event)Telaprevir n = 295 Serious adverse events (SAEs)*535 in 160 patients (54.2%) Premature discontinuation / due to SAEs139 (47.1%) / 63 (21.3%) Death 7 (2.4 %) Infection (Grade 3/4) † 27 (9.1 %) Hepatic decompensation (Grade 3/4)15 (5.1 %) Rash (grade 3/SCAR)16 (5.4 %) / 2 (0.6 %) Anemia (Grade 3/4 : Hb < 8 g/dL)38 (12.9 %) EPO use / blood transfusion168 (57 %) / 53 (18 %) GCSF use8 (2.7 %) TPO use6 (2 %) *SAEs in patients; SCAR: severe cutaneous adverse reaction † 3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection INF + Riba +Telaprevir: SVR12 safety findings

Patients, n (% patients with at least one event)Boceprevir n = 190 Serious adverse events (SAEs)*321 in 97 patients (51.0%) Premature discontinuation / due to SAEs80 (42.1%) / 27 (14.2%) Death † 3 (1.6 %) Infection (Grade 3/4)8 (4.2 %) Hepatic decompensation (Grade 3/4)9 (4.7 %) Rash (grade 3/SCAR)2 (1.0 %) Anemia (Grade 3/4: Hb < 8 g/dL)19 (10.0 %) EPO use / blood transfusion119 (62.6 %) / 26 (13.7 %) GCSF use13 (6.8 %) TPO use3 (1.6 %) *SAEs in patients; SCAR: severe cutaneous adverse reaction † 1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia INF + Riba + Boceprevir: SVR12 safety findings

Antiviral activity in all HCV genotypes No/less selection of resistance All-oral combination regimen Short treatment duration 6-12 weeks QD (or BID) dosing Excellent safety and tolerability Less or no DDI Applicable in difficult-to-treat populations:  Transplant  Coinfection  End-stage renal disease, etc. Applicable in difficult-to-treat populations:  Transplant  Coinfection  End-stage renal disease, etc. HCV — The Revolution Has Begun

Interferon Ribavirin Pegylated interferons Proof of concept for DAA (PI) Suppression of HCV with DAA combination (PI + NI) Telaprevir and boceprevir Curability of HCV without Interferon Target >90% SVR reached in Phase II and III trials Frequent curability of diverse populations without IFN Approval of simeprevir and sofosbuvir with IFN:G1, others? First approved IFN-free therapy: SOF+RBV: G2, 3 IFN-free DAA combinations (G1) SVR % Potential approval of other DAAs with IFN (eg faldaprevir) HCV Therapy—Past, Present, and Future Thank you to Dr Ira Jacobson

Two New Protease Inhibitors are coming in combination with PEG IFN/RBV Simeprevir  NS3 protease Inhibitor  Q daily dosing  Improved side effect profile  No anemia  Fewer DDIs Faldaprevir  NS Protease inhibitor  Q daily dosing  Improved side effect profile  No anemia 18

Simeprevir (TMC 435) HCV-specific NS3/4A protease inhibitor Antiviral activity in patients infected with GT 1, 2, 4, 5, and 6 Oral, once-daily tablet Limited drug-drug interactions as CYP 3A4 inhibitor only at level of intestine Safe and well tolerated, n ~3800 patients

Simeprevir—Completed Phase III Studies QUEST-1 and QUEST-2  Same study design, but conducted independently of each other  Treatment-naïve GT 1 patients PROMISE  Same study design as QUEST-1 and QUEST-2  GT 1 prior relapsers Jacobson I, et al. EASL 2013, Abstract Manns M, et al. EASL 2013, Abstract Lawitz E, et al. DDW 2013, Abstract 869b.

SMV 150 mg/ PEG/RBV PEG/RBV Posttherapy follow-up Response-Guided Treatment Placebo/ PEG/RBV Posttherapy follow-up Weeks QUEST-1, QUEST-2, and PROMISE Study Designs Response-guided therapy: if HCV RNA <25 IU/mL at week 4 and undetectable at week 12, complete treatment at week 24  85%−93% of patients met the criteria and qualified for total treatment duration of 24 weeks Jacobson I, et al. EASL 2013;Abstract Manns M, et al. EASL 2013;Abstract Lawitz E, et al. DDW 2013; Abstract 869b.

Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment-Naïve and Prior Relapsers 210/ / / / / / * 50 81* 50 79* 37 *P<0.001 Jacobson I, et al. EASL 2013;Abstract Manns M, et al. EASL 2013;Abstract Lawitz E, et al. DDW 2013; Abstract 869b.

QUEST-1—SVR by Subgroup Jacobson I, et al. EASL 2013;Abstract FibrosisGenotypeIL28B genotype Q80K polymorphism affected SVR / /9054/7711/40 105/ /74 105/ /5672/7729/37 114/ /7624/374/17

QUEST-2—SVR by Stage of Fibrosis Jacobson I, et al. EASL 2013;Abstract Manns M, et al. EASL 2013;Abstract Lawitz E, et al. DDW 2013; Abstract 869b /19552/10224/369/1711/176/15

ASPIRE—Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders SMV 100 mg* + PEG/RBV SMV 150 mg* + PEG/RBV Placebo + PEG/RBV *For each dose, SVR for different treatment durations were similar so results were pooled. Abbreviation: SMV, simeprevir. Zeuzem S, et al. EASL 2012;Abstract SVR24 (%) RelapsersPartial RespondersNull Responders n = 100

QUEST-2—Safety Profile Adverse Events SMV/PR (n = 257) Placebo/PR (n = 134) Grade 1 or 2 AE Grade 3 or 4 AE Serious AE AE leading to discontinuation of SMV * Most common AEs (≥25% in SMV arm) Headache Pyrexia Fatigue Influenza-like illness Other AEs of interest Rash (any type) Anemia Pruritus Photosensitivity conditions  Data for the first 12 weeks of treatment are shown  The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2 *Without regard to PEG IFN and RBV. Abbreviations: AE, adverse event; PR, PEG IFN + ribavirin; SMV, simeprevir. Manns M, et al. EASL 2013;Abstract Patient %

Simeprevir—Benefits Virtually all patients qualify for short-duration (24 weeks) therapy Limited drug-drug interactions Daily dosing

Simeprevir—Data Gaps GT 2 and 4 subtypes Phase III data in prior PEG/RBV partial and null responders Renal disease Pre and post transplant

Simeprevir + PegIFN/RBV for Treatment-naïve Patients with GT 1 Infection Simeprevir: Once daily HCV protease inhibitor Quest 1 and 2 trial: GT 1, treatment naïve patients (n=785) Simeprevir 150 mg or placebo for 12 wks + PegIFN/RBV for 24 or 48 weeks (RGT) 88% had HCV RNA < 25 IU/mL at week stop after 24 weeks: SVR 88% Discontinuation due to AE was 3% : Increase in bilirubin and phototoxicity ; no anemia In subjects with the Q80K polymorphism at baseline, no statistically significant difference in SVR12 rates was observed *In subjects with the Q80K polymorphism at baseline, no statistically significant difference in SVR12 rates was observed * Q80K prevalence in 1500 clinical specimens sent to an US commercial labQ80K prevalence in 1500 clinical specimens sent to an US commercial lab −GT 1a, 32.5% −GT 1b, 0.1% * 95% confidence intervals 38.0 (27.4; 48.5) * 50.6 (37.5; 63.7) * 9.9 (-11.9; 31.7) * 35.9 (24.6; 47.3) * Jacobson I, et al. 64th AASLD; Washington, DC; November 1-5, Abst Abstract 1122; FDA AVDAC *; Choe SS et al The Liver Meeting Abstract 1500

Prevalence of Q80K Mutations by Region in Phase III Simeprevir Studies Lenz O, et al. 64th AASLD; Washington, DC; November 1-5, Abst n/N (%) All HCV GT HCV GT1a HCV GT1b Overall274/2007 (13.7)269/911 (29.5)5/1096 (0.5) Europe76/1254 (6.1)73/377 (19.4)3/877 (0.3) North America185/538 (34.4)185/385 (48.1)0/153 (0) South America2/60 (3.3)2/22 (9.1)0/38 (0) Includes 15 subjects with non-1a/b GT GT, genotype; HCV, hepatitis C virus FDA mandates Q80 polymorphism testing when using simeprevir

All Oral: Sofosbuvir plus Ribavirin Genotype 2 and 3* Jacobson IM, et al.. N Engl J Med 2013;368: Weeks of Treatment: (N=100) (N=95) *Patients with previous non-response to IFN-based treatment

All Oral: Sofosbuvir plus Ribavirin Cirrhosis vs No Cirrhosis Jacobson IM, et al.. N Engl J Med 2013;368: Weeks of Treatment: Genotype 3Genotype 2 (N=100) (N=95) 25/ 26 23/ 23 6/ 10 7/ 9 14/ 38 25/ 40 5/ 26 14/ 23

Sofosbuvir + RBV VALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures Sofosbuvir + RBV VALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures SOF+RBV (n=73) SOF+RBV (n=250) SVR12 =93% G2 G3 Genotype Naïve Treatment-experienced Noncirrhotic Cirrhotic SVR 12 (%) 86/92 12/13 85/100 27/45 FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085 Wk 0 Wk 24

Sofosbuvir/PegIFN/Ribavirin Genotype 1 (N=327) Lawitz E, et al. N Engl J Med 2013;368:

Abstract #LB-3 SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS- 7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study Ira M. Jacobson 1, Reem H. Ghalib 2, Maribel Rodriguez-Torres 3, Zobair M. Younossi 4, Ana Corregidor 5, Mark S. Sulkowski 6, Edwin DeJesus 7, Brian Pearlman 8, Mordechai Rabinovitz 9, Norman Gitlin 10, Joseph K. Lim 11, Paul J. Pockros 12, Bart Fevery 13, Tom Lambrecht 14, Sivi Ouwerkerk-Mahadevan 13, Katleen Callewaert 13, William T. Symonds 15, Gaston Picchio 16, Karen Lindsay 16, Maria Beumont-Mauviel 13, Eric Lawitz Weill Cornell Medical College, New York, NY, United States. 2. Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, United States. 3. Fundación de Investigación, San Juan, Puerto Rico, United States. 4. Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States. 5. Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, United States. 6. Johns Hopkins University School of Medicine, Baltimore, MD, United States. 7. Orlando Immunology Center, Orlando, FL, United States. 8. Atlanta Medical Center, Atlanta, GA, United States. 9. University of Pittsburgh Medical Center, Pittsburgh, PA, United States. 10. Atlanta Gastroenterology Association, Atlanta, GA, United States. 11. Yale School of Medicine, New Haven, CT, United States. 12. Scripps Clinic, La Jolla, CA, United States. 13. Janssen Research & Development, Beerse, Belgium. 14. Novellas Healthcare, Zellik, Belgium. 15. Gilead Sciences Inc, Foster City, CA, United States. 16. Janssen Research & Development LLC, Titusville, NJ, United States. 17. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States.

Background Simeprevir (TMC435) is an investigational, one pill, once-daily, potent oral HCV NS3/4A protease inhibitor recently approved in Japan and currently under regulatory review in North America and Europe Sofosbuvir (GS-7977) is an HCV nucleotide NS5B polymerase inhibitor also currently under regulatory review COSMOS is a Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin Interim analysis

COSMOS: Study design Cohort 1: Prior null responders (METAVIR F0-F2) Final SVR12 for all arms Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4) Interim SVR4 for Arms 3 and 4 SMV + SOF + RBVPost-treatment follow-up Arm 1 Week SMV + SOF SMV + SOF + RBV SMV + SOF Post-treatment follow-up Arm 2 Arm 3 Arm 4 Enrolment ratio 2:1:2:1 N=14 N=24 N=14 N=27

24 week treatment 13/14 26/27 SMV/SOF 12 wks SMV/SOF/RBV 12 wks SVR12 (SMV/SOF) SVR12 (SMV/SOF/RBV) 1/27 1/14 14/1419/24 SMV/SOF 24 wks SMV/SOF/RBV 24 wks Patients (%) 1/24 4/24 Non-virologic failure Relapse Cohort 1: Null responders (F0-2) 12 week treatment

Patients (%) 1/27 SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) 12 week treatment 7/712/127/714/15 1/15 Relapse 26/27 14/14 Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4 9 naïve and 9 null responders METAVIR F4 patients Only relapser was a F4 prior null responder

Most Common AEs: Cohorts 1 and 2 combined 12 weeks24 weeks Patients, n (%) SMV + SOF (n=28) SMV + SOF +RBV (n=54) SMV + SOF (n=31) SMV + SOF + RBV (n=54) Total (n=167) Fatigue7 (25.0)13 (24.1)10 (32.3)20 (37.0)50 (29.9) Headache6 (21.4)9 (16.7)7 (22.6)11 (20.4)33 (19.8) Nausea6 (21.4)8 (14.8)4 (12.9)6 (11.1)24 (14.4) Insomnia4 (14.3)5 (9.3)2 (6.5)9 (16.7)20 (12.0) Rash1 (3.6)8 (14.8)3 (9.7)7 (13.0)19 (11.4) Pruritus3 (10.7)5 (9.3)1 (3.2)9 (16.7)18 (10.8) Anemia06 (11.1)1 (3.2)11 (20.4)18 (10.8) *At least one study drug AE, adverse event; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir

Conclusion Treatment with SMV + SOF ± RBV results in:  High SVR12 rates in HCV GT 1 null responder patients  High SVR4 rates in naïve and null-responder patients with METAVIR F3-F4 These findings suggest that addition of RBV to SMV + SOF may not be necessary to achieve good virologic response in this patient population 12 weeks’ treatment may confer similar clinical benefit to 24 weeks’ treatment SMV + SOF ± RBV was generally well tolerated

IFN-free Summary Cross-company Studies WeeksSVR Daclatasvir + Sofosbuvir (N=41, GT-1)12100% Simeprevir + Sofosbuvir COSMOS (N=80)12100% Sulkowski MS, et al. EASL 2013; abstract Lawitz EM, et al. CROI 2013; abstract 155LB.

IFN-free Summary Phase 2 Study Results WeeksSVR ABT450/r + ABT267 + ABT333 + RBV (N=571) 12~90% Sofosbuvir + ledipasvir + RBV (N=34) % Faldaprevir + deleobuvir + RBV (GT1b, N=20) 16~95% DCV + ASV + BMS (N=66) % Kowdley K, et al. EASL 2013; abstract 3. Gane E, et al. CROI 2013; abstract 41LB. Zeuzem S, et al., APASL Everson GT, et al. IDSA 2013; abstract 1828.

Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q Projected Timing for New Regimen Launches Sofosbuvir + RBV GT2/3, Naïve/Tx- EXP/ IFN Ineligible TX-Exp BMS DCV/ASV/RBV* GT1b Naïve/Tx-Exp/ IFN Intolerant Daclatasvir Triple Gt1. Naïve only Sofosbuvir + lepedisvir GT1/2/3, Naïve/TX- EXP/ IFN Ineligible ABT- 450/267/333/RBV ---- GT1, Naïve/Tx-EXP Faldaprevir (BI201335) Triple ---- GT1 Naïve, Tx-EXP Sofosbuvir Triple ---- GT1, 4, 5, 6, Naive Simeprevir Triple ---- GT1, Naïve, Tx- Exp Triple IFN-Free * Precise timing TBD COSMOS Study Off Label use SOF + SIM G-1

To Treat or not to Treat: A Constellation of Considerations Duration of infection Personal plans (marriage, pregnancy) Age COST HIV coinfection Extrahepatic Features (Fatigue, EMC, PCT) Patient "mindset" Genotype virus Genotype Patient (IL28) Q80K mutation or others Contraindications & comorbidities Insulin Resistance Histologic stage 20%+ life time risk Of cirrhosis Family and other support Occupation To Treat or not to Treat: A Constellation of Considerations