2. Treatment-experienced HCV genotype 1 patients Bill Sievert Sally Bell

3. Learning objectives Review definitions of treatment failure and characterisation of previous treatment episodes Understand the impact of interferon sensitivity on DAA treatment outcomes Review treatment outcomes in non-cirrhotic and cirrhotic patients Understand the impact of viral resistance Review futility rules in DAA regimens

4. Ms CM 45-year-old woman with HCV genotype 1 referred for assessment in 2003 Prior IDU Current medications: milk thistle, glutamine, vitamins C/E, ‘liver detox’ and ‘liver gourd’ tablets No EtOH Past history – migraines Family history – eczema, alcoholism

5. Ms CM US – cholelithiasis, normal spleen and liver Liver biopsy – Metavir F3, steatohepatitis

6. Ms CM – 2004 Peg-IFN 2a 180 µg + RBV 1000 mg x 48 weeks On-treatment adverse events – Depression, treated with sertraline – Diarrhoea, treated with loperamide

7. Ms CM – 2004 Virological outcomes – Pre-treatment5.60 log IU/mL – Week 123.58 log IU/mL – Week 24<2.78 log IU/mL – Week 34not detected – End of treatment (Wk 48)not detected – Follow-up Wk 12detected How would you characterise her virological response?

8. Definitions What’s in a name? Relapse Undetectable HCV RNA at the end of treatment but detectable HCV RNA during follow-up Partial responder ≥2 log 10 decline in HCV RNA at week 12 but detectable at week 24 during therapy Null responder <2 log 10 decline in HCV RNA at week 12

9. Challenges in categorising previous treatment response Lack of detailed records Lack of patient evaluation at key time points on previous therapy Differentiation of previous partial response vs null response – May be unable to characterise decline in HCV RNA levels at key times

10. Ms CM – 2008 Liver tests – Bilirubin6 µmol/L – ALT39 U/L – Albumin39 g/L – Hb158 g/L – Platelets244 X 10 9 /L – INR0.9 Liver biopsy – F 3/4 Genotype 1a What would you advise her to do now?

11. Boceprevir and Telaprevir Telaprevir – ADVANCE: Treatment-naïve patients – ILLUMINATE: Response-guided therapy (treatment naïve) – REALIZE: Treatment-experienced patients (relapse, null and partial response) Boceprevir – SPRINT-2: Treatment naïve patients – RESPOND-2: Treatment-experienced patients (relapse and partial response) Potent inhibitors of HCV NS3/4A protease Both tested in combination with standard-of-care peg-IFN alfa/RBV in phase III studies in chronic HCV genotype 1 infection

12. Week 4Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir PR lead-in Week 36Week 72 TW 8 HCV-RNA Undetectable TW 8 HCV-RNA Detectable TW 12 Undetectable PR + placebo Follow-up RESPOND – BOC in relapse + partial responders Control 48 P/R (n=80) BOC RGT (n=162) Boceprevir dose: 800 mg tds PR + Boceprevir PR lead-in Follow-up BOC/ PR48 (n=161) HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12 were considered treatment failures. Week 12 futility New Engl J Med 2011;364:1207-17

13. PR PR + TVR REALIZE: TVR in HCV relapse, partial response and null responders PR PR + TVR n=132 n=264 n=266 PR Week 12Week 16Week 48Week 72Week 4 Lead-in Follow-Up N Engl J Med. 2011;364:2417-28.

14. Boceprevir and telaprevir improve SVR rates in naïve and experienced patients SOC, standard of care SVR, sustained virologic response 1. Poordad F, et al. NEJM 2011;364:1195-206; 2. Jacobson IM, et al. NEJM 2011;364:3405-16. 3. Bacon BR, et al. NEJM 2011;364:1207-17; 4. Zeuzem S, et al. NEJM 2011;364:2417-28. 0 20 40 60 80 100 SVR (%) Treatment-naïve patients 1,2 38–44 Current Standard of Care 63–75 SOC + Protease Inhibitor Δ~ 30% Treatment-experienced patients 3,4 17–21 0 20 40 60 80 100 SVR (%) 59–66 Current Standard of Care SOC + Protease Inhibitor Δ~ 40%

15. Ms CM – 2008 Enters REALIZE study: TPV 750 mg 8-hourly or placebo + peg-IFN 180 µg/RBV 1200 mg Virological outcomes – Pre-treatment6.23 log IU/mL – Week 44.81 log IU/mL – Week 123.35 log IU/mL – Week 241.66 log IU/mL – FU Week 245.83 log IU/mL Virological response = ‘non-responder’

16. Ms CM – 2010 Assigned to placebo arm in main study; enters open-label roll-over study: TPV + peg-IFN/RBV Virological outcomes – Pre-treatment6.16 log IU/mL – Week 4not detected – Week 12not detected – Week 24not detected – Week 48not detected – FU Week 24not detected Virological response = SVR = cure

17. Relapser SVR (%) 59%* 83%* 54%* 0 20 40 60 80 88%* 15% 29%* P/R 48 T12/PR 48 24% Non- responder 9% 41%* 5% 33%* T12/PR 48, Lead-in Null responder Partial responder REALIZE: SVR rates according to treatment arm and prior response N Engl J Med. 2011;364:2417-28. 17

18. HCV Genotype 1a vs 1b GT nucleotide sequences differ by 30-35% Subtypes differ by 20-25% Genotype 1a less susceptible to NS3 protease, NS5B polymerase, NS5a inhibitors than 1b – Pre-existing mutations more frequent in 1a than 1b – 1a requires only one mutation; 1b requires two (1a has lower genetic barrier to resistance) – Higher rate of virological failure with genotype 1a Kuntzen, et al. Hepatology 2008;48:1769. Gao, et al. Nature 2010;465:96.

19. REALIZE (telaprevir): SVR by HCV subtype and prior response to peg-IFN/RBV 123/140 n/N= 6/3110/34119/14227/401/103/1626/5522/591/201/1724/88 1a1b HCV subtype 1a SVR (%) Zeuzem S, et al. J Hepatol 2011;54(Suppl 1):S3. Prior relapsers Prior partial responders Prior null responders Pbo/PR 48 Pooled T12/PR 48 19

20. REALIZE (telaprevir): SVR rates by IL28B genotype and prior response to peg-IFN/RBV Pol S, et al. J Hepatol 2011;54(Suppl 1):S6. Prior relapsers SVR (%) Prior partial responders Prior null responders Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) CCCT TT CCCT TT CCCT TT 4/12 51/58 6/30100/1173/1029/341/55/82/1033/570/510/144/101/1827/921/1510/32 n/N= n/a 20

21. Response-guided therapy – Telaprevir Non-cirrhotic treatment-experienced patients RGT for previous relapse Full 48 weeks for partial or null response

22. Response-guided therapy – Boceprevir Non-cirrhotic treatment-experienced patients RGT for previous relapse and partial response Full 48 weeks for null responders

23. Mr AB 46-year-old man Office manager HCV diagnosed during insurance examination HCV genotype 1b Blood transfusion at birth (Rh- mother); ‘blood brother’ ritual at age 8 years

24. Mr AB – 2000 Bilirubin17 µmol/L ALT254 U/L Albumin43 g/L Hb177 g/L Platelets252 x 10 9 /L INR1.0

25. Mr AB – 2000 Standard IFN 3 MU tiw + RBV 1200 mg/day (December 2000 – August 2001) Virological outcomes – Pre-treatment9.51 MEq/mL * – Week 12detected – Week 24detected – Week 36detected (ceases Rx) Virological response = ‘non-responder’ * Mega equivalents/mL; Chiron bDNA assay

26. Mr AB – 2003 EPIC 3 study* – peg-IFN 1.5µg/kg/wk + RBV 1200 mg/day x 12 wk If response  complete 48 wk, if not, maintenance peg-IFN or observation Virological outcomes – Pre-treatment5.61 log IU/mL – Week 124.88 log IU/mL Virological response = null responder Randomised to observation arm (36 months) *Gastroenterology 2009;136(5):1618-28.

27. Mr AB Poor response to IFN-based regimens in two prior treatment episodes Will IFN responsiveness have an impact on DAA treatment?

28. Concept of lead-in phase Identify interferon-responsive patients Decrease risk of resistance to direct-acting agents Avoid costs and side-effects of direct-acting agents PEG IFN + RBV PEG IFN + RBV + direct acting agent PEG IFN + RBV 4 weeks RVR No RVR

29. SVR by Week 4 PR lead-in response Poorly responsive to IFN <1 log 10 viral load decline at treatment week 4 Responsive to IFN ≥1 log 10 viral load decline at treatment week 4 0 12 15 46 15 44 17 67 80 110 90 114 SVR (%) PR 48 BOC RGT BOC/PR 48

30. Predictive value of response to lead-in in treatment-experienced patients

31. Mr AB Liver biopsy: Feb 2003Metavir F2 Dec 2006Metavir F3 Dec 2008Metavir F3 “moderate fatty change” “at least incomplete cirrhosis” What is the significance of cirrhosis in DAA treatment regimens?

32. REALIZE: SVR by baseline fibrosis stage and previous response N Engl J Med 2011;364:2417-28. Cirrhosis in combination with prior null response has low SVR

33. Interim analysis of Compassionate Use of Protease Inhibitors in Viral C Cirrhosis (CUPIC) National, multicentre, prospective, observational study of French early-access program Inclusion criteria: – Genotype 1 HCV with compensated cirrhosis (Child-Pugh A) – Previous relapse or partial response to peg-IFN/RBV Patients with null response theoretically excluded (<2 log 10 decrease in HCV RNA at Week 12), although some mistakenly included Primary endpoint: SVR Hezode C, et al. EASL 2012

34. Treatment regimen peg-IFN α-2a + RBV TVR + peg-IFN α-2a + RBV Follow-up 48 4 16012 8 Weeks 72 SVR assessment BOC + peg-IFN α-2b + RBVFollow-up peg-IFN + RBV 36 http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf BOC: 800 mg/8h; peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR: 750 mg/8h; peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day Interim analysis

35. Telaprevir: Preliminary efficacy data 0 20 40 60 80 100 Week 4 Week 8 Week 12 Week 16 53 8586 % of patients with undetectable HCV RNA 145/276 145/285 224/265 219/254 177/205 51 79 78 71 145/285 224/282 219/281 177/251 Per Protocol ITT

36. Boceprevir: preliminary efficacy data 0 20 40 60 80 Week 4 Week 8 Week 12 Week 16 % of patients with undetectable HCV RNA 1 37 37 61 2/155 55/149 88/144 89/126 2/155 55/150 58 61 88/151 89/146 71 Per Protocol ITT

37. Main findings Telaprevir- and boceprevir-based regimens: high rates of SAEs in real-world setting 6 deaths in telaprevir group: sepsis (n=2), pneumopathy (n=1), bleeding of oesophageal varices (n=1), encephalopathy (n=1), and lung carcinoma (n=1) 2 deaths in boceprevir group: bronchopulmonary infection (n=1) and sepsis (n=1) SAE in 38% (BOC) and 49% (TPV) : – High rates of discontinuation because of AEs (7% to 15%) – Grade 3/4 anaemia common with both regimens and responds poorly to erythropoietin Treat cirrhosis patients cautiously; carefully monitor because of a high incidence of anaemia with poor response to EPO and risk of sepsis Hezode C, et al. EASL 2012

38. Mr AB – 2008 Bilirubin17 µmol/L ALT 232 U/L Albumin38 g/L Hb180 g/L Platelets184 x 10 9 /L INR1.1

39. Mr AB – 2008 Enters REALIZE study: TPV 750 mg 8-hourly or placebo + peg-IFN 180 µg/RBV 1200 mg Widespread rash – Day 3: Mild (Rx promethazine) – Week 4: Rash improving (promethazine, Kerri Oil baths, betamethasone cream) – Week 10: “Patchy discoid rash on legs” – Week 12: “Macular rash both legs, lower back” – Week 20: “Discoid erythematous areas of rash”

40. Adverse events associated with NS3 protease inhibitors in clinical trials Alfa=peg-IFN alfa RBV=ribavirin 1. Victrelis™ (boceprevir) US prescribing information. May 2011. 2. Incivek™ (telaprevir) US prescribing information. May 2011. Adverse Event (%) * Boceprevir + alfa-2b/RBV (n=1225) Alfa-2b/RBV (n=467) Anaemia5030 Dysgeusia3516 Adverse Event (%) † Telaprevir + alfa-2a/RBV (n=1797) Alfa-2a/RBV (n=493) Rash5634 Pruritus4728 Nausea3928 Anaemia3617 Telaprevir 2 Boceprevir 1 * Events occurring at ≥10% with boceprevir+alfa-2b vs alfa-2b/RBV alone in treatment-naïve patients † Events occurring at ≥10% with telaprevir+alfa-2a/RBV vs alfa/RBV alone in treatment-naïve and -experienced patients

41. Mr AB – 2008 Virological outcomes – Pre-treatment6.95 log IU/mL – Week 4<25 IU/mL – Week 12<25 IU/mL – Week 242.33 log IU/mL (216 IU/mL) What is happening? – FU Week 46.17 log IU/mL – FU Week 246.47 log IU/mL

42. Mr AB Converted a null response to peg-IFN/RBV to a breakthrough response to triple therapy Could antiviral resistance to telaprevir contribute to his non-response?

43. Antiviral resistance Barriers to resistance – Genetic: number of amino acid substitutions needed for mutant to acquire full resistance 1 substitution = low barrier 3+ substitutions = high barrier – In vivo fitness and drug exposure Low Barrier DAA – First-generation protease inhibitors (telaprevir, boceprevir) – NS5A inhibitors – Non-nucleoside polymerase inhibitors High barrier DAA – Nucleoside polymerase inhibitors – Cyclophilin inhibitors – ? Second-generation protease inhibitors J-M Pawlotsky. J Hepatol 2012;56:11

44. REALIZE: TVR-resistant variants associated with virologic failure in the TVR/placebo treatment phase LI T12/PR 48 (n=149) T12/PR 48 (n=136) V36M+R155K A156T/V Combinations Not available Wild-type (no TVR-resistant variants) LI T12/PR 48 (n=113) T12/PR 48 (n=126) V36A/M T54A/S R155I/K/M/T A156S Combinations 20 25 15 10 5 0 20 25 15 10 5 0 Number of patients Genotype 1aGenotype 1b Lower-levelHigher-level Analysis used population-based sequencing. On-treatment virologic failure: patients who discontinued due to a virologic stopping rule and/or patients with viral breakthrough De Meyer, et al. J Hepatol 2011;54:S475

45. CONFIDENTIAL. FOR ADVISORY BOARD USE ONLY. Not for further distribution. Viral kinetics in patients meeting the >1000 IU/mL HCV RNA Week 4 stopping rule with telaprevir Jacobson I, et al. EASL 2012. Abstract 45 Treatment-naïve patientsTreatment-experienced patients 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10 0468 12 102 Weeks HCV RNA (IU/mL) 0468 12 102 Weeks HCV RNA (IU/mL) 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10

46. Futility rules – Boceprevir Treatment-naïve and treatment-experienced Jacobson I, et al Hepatology 2012; Accepted Article, doi: 10.1002/hep.25865

47. Futility rules – Telaprevir Treatment-naïve and treatment-experienced

48. Mr AB – 2012 What can you offer this patient with: Cirrhosis and persistent ALT elevation? Null response to peg-IFN/RBV Breakthrough/partial response to TPV + peg- IFN/RBV Re-treat with boceprevir? Refer for clinical trial?

49. Simple, all-oral, pan-genotypic regimens? Alfa/Lambda + RBV Improved tolerability Favourable IL28B genotypes DUAL: 1-2 x DAAs (±RBV) IFN ineligible/intolerant Genotype 1b, 2/3 Future treatment options for HCV Alfa, peg-IFN alfa; DAA, direct-acting antiviral; IFN, interferon; Lambda, peg-IFN lambda-1a; RBV, ribavirin QUAD: IFN/RBV + 2 x DAAs Difficult-to-treat Null/non-responders Cirrhotics TRIPLE: IFN/RBV + DAA Shortened duration Improved tolerability

50. Modeling first-line DAAs vs Quad therapy for null responders Treat F3/4 with DAA now vs quad therapy in 5 yrs Assumptions: – SVR TPR 42% F3, 14% F4; Quad 90% SVR – Quad rescue AFTER TPR –> PI resistance 80%: SVR reduced by 70% Ewan et al # 991 EASL 2012

51. Using DAAs in treatment-experienced patients Assess prior response, histology, subtype – Relapsers likely to do well on either DAA, even if cirrhotic – Null or partial responders who are cirrhotic, G1a are likely to do poorly SVR low, resistance high 1a >1b (-> need 2 DAAs) Risk of sepsis and SAE significant: Check CP score, MELD Consider trials using quad therapy – Null or partial responders, non cirrhotic, G1b DAAs (SVR 40-55%), trials (new trials 80-90%) or wait