Michael Fried, MD University of North Carolina Chapel Hill, NC. Ira Jacobson, MD Weill Cornell Medical College New York, NY

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Nezam Afdhal, MD Beth Israel Deaconess Medical Center Boston, MA Kim Brown, MD Henry Ford Hospital Detroit, MI Michael Fried, MD University of North Carolina

Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ).

1 Nezam Afdhal, MD Beth Israel Deaconess Medical Center Boston, MA Kim Brown, MD Henry Ford Hospital Detroit, MI Michael Fried, MD University of North Carolina Chapel Hill, NC Jordan Feld, MD Toronto Western Hospital Liver Center Toronto, Canada Ira Jacobson, MD Weill Cornell Medical College New York, NY Supported by: Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ). This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex Pharmaceuticals. This is not an official function/event of the American Association for the Study of Liver Diseases. Sponsored by:

2 Welcome Tonight s News Program Field Report Breaking News on New CDC Recommendations Michael Fried, MD Case #1 Treat Now or Wait for Future Therapies Kim Brown, MD; Jordan Feld, MD Field Report Breaking News on Real-World Clinical Data Ira Jacobson, MD Case #2 Optimizing Outcomes with Current Treatments Kim Brown, MD; Jordan Feld, MD Press Conference: Late Breaking Data, Q&A

3 Glenn: Patient Characteristics 55 year old male Shift worker History/risk factors BMI=34 Hypertension and dyslipidemia Moderate drinker/cigarette smoker Concomitant medications Simvastatin 20 mg/day Lisinopril 10 mg/day

4 Glenn: Baseline Labs Hemoglobin 15.6 g/dl Neutrophils 1400 cells/mm 3 Platelets 210,000 cells/mm 3 AST/ALT 55/75 IU/L Albumin 4.1 g/dl Bilirubin 0.7 mg/dl

5 Glenn: Disease Characteristics Treatment naïve Genotype 1a IL28B CC METAVIR F3 BL viral load 1,300,000 IU/mL

6 ARS #1 How would you manage this patient? 1. Continue to monitor patient but do not start treatment 2. Start patient on first generation protease inhibitor/peg-ifn/rbv

7 Modeling of Liver Fibrosis in Chronic Hepatitis C n=1157 Patients F Metavir 4 Rapid progressors Intermediate progressors 3 2 Slow progressors Poynard et al, Hepatology 1999 Years

8 Proportion of Patients Cumulative Proportion of Patients Transitioning from Compensated to Decompensated Stage Over Time Pts at risk months D Amico G et al. J Hepatol. 2006;44:

21% 12% 60% 43% 36% 40% 86% 20% 36% 43% 0% *Necrosis and Inflammation.

9 % of patients Impact According to Response of 10 Different Treatment Regimens on Evolution of Activity* in 3010 Patients with Paired Biopsies 100% 80% Improved Stabilized Worsened 2% 21% 21% 12% 60% 43% 36% 40% 86% 20% 36% 43% 0% *Necrosis and Inflammation. Non-responders (n=1452) Poynard et al. Gastroenterology, 2002;122: Relapsers (n=464) Sustained responders (n=1094)

10 ADVANCE: IL28B Genotype Effect on Telaprevir Therapy In Patients Tested for IL28B (%) CC CT TT Total In All ADVANCE Patients T12PR* T8PR** PR *T12PR = T+PR12 weeks, then PR12 or 36 weeks depending on ervr status **T8PR = T+PR8 weeks, then PR16 or 40 weeks depending on ervr status Jacobson et al. EASL 2011

11 SVR SVR Rates in F1/2 vs F3/4 Naïve Patients % F1/2 F3/4 76% 67% % Boceprevir Telaprevir Jacobson IM et al, NEJM, 2011; 364: Poordad F et al, NEJM, 2011; 364:

12 OPTIMIZE Trial: Telaprevir BID vs TID PR + TVR 1125 mg BID versus 750 mg TID Response-guided therapy 740 patients 29% bridging fibrosis or cirrhosis 57% G1a, IL28B CC 29% Buti M et al, Abstract LB-8, AASLD 2012

13 OPTIMIZE Trial: Results 100 TVR 1125 mg BID 80 69% 67% TVR 750 mg TID 74% 73% (%) Buti M et al, Abstract LB-8, AASLD 2012 RVR SVR

14 Should Glenn Be Treated Now? F3 disease risk of progression with waiting IL28B CC Potential BID option is attractive I would treat

15 The Case for Waiting Multiple issues with current therapy Compliance pill burden Co-morbidities Adverse effects

16 Compliance Pill Burden Food Requirement BOC = 18/d TVR = 12/d RBV 4-7/d RBV 4-7/d

17 Co-Morbidities Cardiac Risk Factors Hypertension, hyperlipidemia, smoker Pre Treatment DDI Statin with TVR/BOC likely just stop it On Treatment Anemia management consider pre-treatment cardiac testing

18 Drugs with the Potential to Interact with First Generation Protease Inhibitors are Commonly Used by HCV Patients Mayer et al, Abstract #136, AASLD 2012 Drug Name Percent Drug Name Percent Zolpidem * 17.4 Diazepam 7.9 Codeine 16.0 Bupropion * 7.2 Prednisone 15.4 Trazodone 7.1 Tramadol * 14.3 Fluconazole 6.8 Citalopram 13.5 Sertraline 6.4 Fluticasone 13.1 Clarithromycin 6.1 Methylprednisolone 13 Sildenafil (Viagra) 5.4 Alprazolam * 11.8 Clonazepam 5.3 Amlodipine * 10.2 Simvastatin 5.2 Escitalopram * 8.1 Venlafaxine 5.0 * One of the 20 most frequently filled

19 New Drug-Drug Interaction Data at AASLD 2012: HCV Protease Inhibitors No clinically significant interactions Boceprevir Prednisone (abstract #1896) Omeprazole (abstract #1808) Ethinyl estrodiol/norethidrone (abstract #1901) Simeprevir (TMC-435) Cyclosporine/tacrolimus (abstract #80) Ethinyl estrodiol/norethidrone (abstract #773)

% of patients Anemia is a Known Side Effect with First Generation Protease Inhibitor Based Therapies % of patients 100 90 80 70 60 50 40 30 20 36% 17% TVR PR 100 90 80 70 60 50 40 30 5/5 11/13 13/14

20 % of patients Anemia is a Known Side Effect with First Generation Protease Inhibitor Based Therapies % of patients % 17% TVR PR /5 11/13 13/ % 10 5% 10 3% 0 0 < 10 g/dl < 8.5 g/dl < 10 g/dl < 8.5 g/dl Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November % 28% 7% BOC PR

21 % % Future Options for Waiting? (Short-Term) PILLAR (G1 Naïve) 1 Simeprevir 150 mg OD x 12 wks + PR x PR x 48 SILEN C1 (G1 Naïve) 2 Faldaprevir 240 mg OD x 24 wks + PR x PR x P= P= n/ 62/ 50/ N = SVR 1. Fried et al. AASLD / 77 Met RGT 57/ 61 SVR 20 0 n/ N = 118/ 142 SVR 40/ / 142 Met RGT 53/ 57 SVR 2. Sulkowski et al. EASL 2011

22 No Incremental Decline in Hemoglobin or Neutrophils with Simeprevir or Faldaprevir Anemia with Simeprevir + P/R 1 Anemia with Faldaprevir + P/R 2 1. Jacobson et al, IDSA, Sulkowski et al, EASL 2011

23 Should Glenn Delay Treatment? IL28B CC ~80% chance of shortened therapy % chance of SVR F3 disease risk of progression with waiting No clear issues with IFN Seems anxious and willing to be treated now I would suggest treatment

24 Glenn: On Treatment Response Glenn was started on TVR/PEG/RBV TW4 and TW12 HCV RNA undetectable

25 ARS #2 Which regimen should Glenn receive? weeks TVR/PEG/RBV weeks TVR/PEG/RBV + 12 weeks PEG/RBV weeks TVR/PEG/RBV + 24 weeks PEG/RBV weeks TVR/PEG/RBV + 36 weeks PEG/RBV weeks TVR/PEG/RBV

26 Recommended Treatment Duration Treatment-Naïve and Prior Relapse Patients HCV-RNA Triple Therapy TVR/Peg-IFN/RBV Dual Therapy Peg-IFN/RBV Total Treatment Duration Undetectable at TW4 and TW12 Detectable (<1000 IU/mL) at TW4 and/or TW12 First 12 weeks Additional 12 weeks 24 weeks First 12 weeks Additional 36 weeks 48 weeks Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.

27 HCV-RNA Levels and Lab Assays Undetectable (or target not detected ) result is required for assessing RGT eligibility Below LLOQ but still detectable is not sufficient to shorten therapy ie, patient should continue for full 48 wks LLOQ Values for Various Assays* Assay Name Roche COBAS AmpliPrep/COBAS Taqman HCV Test Roche COBAS Taqman HCV Test, v2.0 LLOQ 43 IU/mL 25 IU/mL Abbott RealTime HCV 4/6 12 IU/mL Assay 13/14 *Package Inserts state the the assay should have a lower limit of HCV-RNA quantification 25 IU/mL and a limit of HCV-RNA detection of approximately IU/mL. Usually considered 25 IU/mL, but 23 IU/mL per FDA-approved label. COBAS AmpliPrep/COBAS Taqman HCV Test. Roche Molecular Diagnostics. Accessed July 19, Harrington PR, et al. Hepatology. 2012;55: United States Food and Drug and Drug Administration (FDA), FDA Division of Antiviral Products; June 30, 2011.

28 Jackie: Patient Characteristics 45 year old African American female History/risk factors BMI=32 CHC diagnosed in 2002 Treated with Peg-IFN/RBV in 2007 Tolerability issues: fatigue, anemia, neutropenia, alopecia, anxiety, depression after 6 months (treated with paroxetine)

29 Jackie: Disease Characteristics Prior relapser (early virologic response) Genotype 1a IL28B CT METAVIR F1 in 2007 BL viral load 18,000,000 IU/mL

30 Jackie: Baseline Labs Hemoglobin 12.1 g/dl Neutrophils 1300 cells/mm 3 Platelets 200,000 cells/mm 3 Serum creatinine 0.9 mg/dl AST/ALT 73/56 IU/L Albumin 4.1 g/dl Bilirubin 0.8 mg/dl INR 0.9

31 ARS #3 Would you reassess stage of fibrosis before retreatment and, if so, how? 1. No, I don t believe it is necessary 2. Yes, I would re-biopsy the patient 3. Yes, I would use non-invasive test

32 ARS #4 Which of the following statements is most accurate? 1. Jackie has a low likelihood of success because she is African American and IL28B CT. 2. Jackie has a very high likelihood of success because she is a prior relapser. 3. If restaging shows cirrhosis, Jackie has a very low chance of success. 4. Treatment is contraindicated for Jackie since she developed depression while on PEG/RBV.

33 %SVR REALIZE: SVR by Response to Previous Peg-IFN/RBV Therapy % All Patients 59% All T12/PR48 Placebo/PR % 15% 32% 5% 0 Relapsers Partial Responders Null Responders Telaprevir (INCIVEK ) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.

34 %SVR RESPOND 2: SVR by Response to Previous Peg-IFN/RBV Therapy % BOC* PR 60 46% % 7% 150/208 16/51 53/115 2/29 Prior Relapsers Partial Responders *Response Guided Therapy and 48 Week Arms Combined Boceprevir (VICTRELIS ) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November 2012.

35 Prior Response Trumps Other Pretreatment Baseline Factors Ethnicity IL28B Genotype Baseline Viral Load Fibrosis Score G1 Subtype

36 Jackie: On Treatment Labs Hemoglobin (g/dl) Neutrophil Count (cells/mm 3 ) HCV RNA (IU/mL) Baseline ,000,000 TW ,300 TW Undetectable

37 ARS #5 How would you manage Jackie s anemia? 1. No change to treatment 2. Add EPO 3. Reduce RBV from 1200 mg to 1000 mg 4. Reduce RBV from 1200 mg to 600 mg 5. Add EPO and reduce RBV (1200 to 600 mg)

38 Boceprevir: No Difference in SVR Rate in Anemic Patients Undergoing RBV DR vs EPO Use % of Patients RBV DR Arm EPO Arm Patients Randomized When Hb <10 g/dl / / / / / 196 EOT Response SVR Relapse Adapted from Poordad F et al. Abstract Poster presented at the 47th Annual Meeting of the European Association for the Study of the Liver. April 2012, Barcelona, Spain. 19/ 197

39 SVR (%; 95% CI) SVR Rates Did Not Vary with the Start Time of Anemia Management / 54 RBV DR 71 39/ 55 Poordad F et al, Abstract 154, AASLD 2012 EPO Use 64 58/ / / 62 4 Wks >4-8 Wks >8-12 Wks >12-16Wks >16 Wks Timing of the Start of Anemia Management 70 47/ / / / / 24

SVR, n/n(%) SVR Rates in Treatment Naïve Patients by RBV Dose/Day 90 80 70 60 50 40 30 20 10 0 74% 74% 75% 329/ 446 47% 29/ 62 291/ 395 42% Any Dose reduction Received 600 mg/day Received 800-1000

40 SVR, n/n(%) SVR Rates in Treatment Naïve Patients by RBV Dose/Day % 74% 75% 329/ % 29/ / % Any Dose reduction Received 600 mg/day Received mg/day 16/ 38 RBV Dose Reductions Never reduced Adapted from Sulkowski MS et al. Abstract Poster presented at the 47th Annual Meeting of the European Association for the Study of the Liver. April 21, 2012, Barcelona, Spain. 38/ 51 54% 13/ 24 79% 346/ % 134/ 292 T12PR PR

41 Jackie: On Treatment Labs Hemoglobin (g/dl) Neutrophil Count (cells/mm 3 ) HCV RNA (IU/mL) Action Baseline ,000,000 TW ,300 TW Undetectable Decreased RBV (1200 to 600 mg/day) TW Undetectable TW Undetectable TW Undetectable TW Undetectable Increased RBV (600 to 800 mg/day) Increased RBV (800 to 1000 mg/day)

42 Jackie: Non-hematologic Adverse Events How do you manage? Constitutional symptoms (fatigue, arthralgia) Mouth sores Rash Anorectal burning Depression

43 LB-2: Daclatasvir (NS5A) + Sofosbuvir (GS-7977, nuc) in GT1a/1b Week 24 SVR 4 SVR 12 SVR 24 SVR 48 n = 15 Group A: SOF 400 mg QD x 7d, then DCV 60 mg QD + SOF 400 mg QD Follow-up n = 14 n = 15 Group C: DCV 60 mg QD + SOF 400 mg QD Group E: DCV 60 mg QD + SOF 400 mg QD + RBV Follow-up Follow-up n = 41 n = 41 Group G: DCV 60 mg QD + SOF 400 mg QD Group H: DCV 60 mg QD + SOF 400 mg QD + RBV Week 12 SVR 4 Follow-Up Follow-Up SVR 48 *12-week groups (G and H) were enrolled after 24-week groups (A, C, and E) RBV: mg/d, weight-based (GT1) Sulkowski MS et al, Abstract LB-2, AASLD 2012

44 HCV RNA < LLOQ (% patients) Virologic Response is Maintained at PT Week 24 (GT1a/1b; 24-Week Treatment Groups) A: SOF LI + DCV C: DCV + SOF E: DCV + SOF + RBV 20 0 n = % of patients with HCV RNA <LLOQ-TND Week 4 EOT SVR 4 SVR 12 SVR 24 Group A: 1 patient with detectable HCV RNA at PT Week 24: HCV RNA cleared 4 weeks later, sequence not consistent with relapse Sulkowski MS et al, Abstract LB-2, AASLD 2012

45 Virologic Response During and After Treatment 12 Week Treatment Groups HCV RNA < LLOQ (% patients) n = Week 4 EOT SVR 4 G: DCV + SOF (12-wk) H: DCV + SOF + RBV (12-wk) % of patients with HCV RNA <LLOQ-TND Group G: 1 patient with missing HCV RNA at PT Week 4 patient achieved SVR 12 Group H: 1 patient with missing HCV RNA at PT Week 4 patient achieved SVR 12 ; 1 patient with HCV RNA < LLOQ-TND at PT week 2 and HCV RNA = 54 IU/mL at PT week 4 (not confirmed) patient achieved SVR 12 Sulkowski MS et al, Abstract LB-2, AASLD 2012

46 LB-3: Daclatasvir (NS5A), Asunaprevir (PI), and BMS (non-nuc) 32 treatment naïve, G1 patients w/o cirrhosis ASV 200 mg BID, DCV 60 mg QD, BMS mg BID (part 2 with 150 mg BID) Patients randomized to 24 vs 12 weeks Majority of patients G1a and non-cc Most common AEs: headache, diarrhea, asthenia Everson G et al, Abstract LB-3, AASLD 2012

47 SVR(%) Daclatasvir, Asunaprevir, and BMS (non-nuc) %* 94%** /16 15/16 Week 12 (24 week group) SVR4 (12 wk group) Everson G et al, Abstract LB-3, AASLD 2012 * One d/c ed early with HCV RNA<LLOQ **One lost to follow up

48 Abstract LB-1: ABT-450/r, ABT-267, ABT-333 +/- RBV in HCV Genotype 1 Treatment Naïve Patients Randomized to treatment for 8, 12, or 24 weeks with: ABT-450/r (Protease inhibitor + ritonavir boost) combined with ABT- 267(NS5A inhibitor) +/- ABT-333 (Non-nuc polymerase inhibitor) +/- Ribavirin Patient characteristics: Non-cirrhotic Genotype 1a = 66% IL28B non-cc= >90% N=438 naïve N=133 prior null responders Kowdley KV et al, Abstract LB-1, AASLD 2012

49 % SVR % SVR LB-1: SVR12 Results % 77/ % 69/ 79 Treatment Naive 96% 52/ 54 83% 43/ 52 Overall G1a G1b 100% 96% % 90 25/ 25 24/ 25 +RBV -RBV Null Responders +RBV 42/ 45 89% 25/ % 17/ 17 Overall G1a G1b +RBV Abbott Press Release, Nov. 10, 2012, Kowdley KV et al, Abstract LB-1, AASLD 2012

50 Abstract 232: Final Results of SOUND-C2 and Predictors of Response Five arm study that evaluated different doses and durations in regimens with faldaprevir (PI) and BI (non-nuc) with or without RBV Durations: 16, 28 or 40 weeks BID vs TID Randomization was stratified by genotype (1a vs 1b) and IL28B 9% of patients had cirrhosis SVR12 ranged between 52% to 69% in RBV-containing arms and 39% without RBV SVR in cirrhotics is 54% IL28B CC, genotype 1b and female gender were favorably associated with SVR12 Zeuzem S et al, Abstract 232, AASLD 2012; Soriano V et al, Abstract 84, AASLD 2012

51 Abstract 229: Once Daily Sofosbuvir (GS-7977) Plus RBV in Patients with HCV G1, 2, and 3: The ELECTRON Trial Evaluate sofosbuvir +RBV as single agent treatment for HCV Small phase IIb exploratory study Non-cirrhotic patients Well-tolerated regimen Prior Null GT 1 Naive GT 1 Experienced GT 2/3 Naive GT 2/3 Naive GT 2/3 Sofosbuvir +RBV Sofosbuvir + RBV Sofosbuvir +RBV Sofosbuvir + RBV Sofosbuvir + RBV (800mg/d) SVR12 1/10 (10%) 21/25 (84%) 17/25 (68%) 16/25 (64%) 6/10 (60%) SVR8 Gilead Press Release, Nov. 10, Weeks

52 Press Conference Q&A

53 Conclusions More patients will be screened, diagnosed and referred into HCV specialty practices as a result of new recommendations Many of these patients are good candidates for treatment today Treatment outcomes with current treatments can be optimized with appropriate management/interventions The HCV pipeline is promising with potential new treatment modalities in the near future

We thank Vertex Pharmaceuticals for the educational grant to support this activity Supported by: Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ).

54 We thank Vertex Pharmaceuticals for the educational grant to support this activity Supported by: Accredited by: Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting ). This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex Pharmaceuticals. This is not an official function/event of the American Association for the Study of Liver Diseases. Sponsored by:

HCV Case Study. Treat Now or Wait for New Therapies

HCV Case Study. Treat Now or Wait for New Therapies HCV Case Study Treat Now or Wait for New Therapies This program is supported by educational grants from Kadmon and Merck Pharmaceuticals. Program Disclosure This activity has been planned and implemented