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Treatment of chronic HCV and predictors of response / IL28B

Treatment of chronic HCV and predictors of response / IL28B. Ola Weiland Karolinska Institutet Karolinska University Hospital. Basic factors favorable vs unfavorable for treatment response. Unfavorable Favorable Genotype 1/4 2/3 Viral load High Low

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Treatment of chronic HCV and predictors of response / IL28B

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  1. Treatment of chronic HCV and predictors of response / IL28B Ola Weiland Karolinska Institutet Karolinska University Hospital

  2. Basic factors favorable vs unfavorable for treatment response Unfavorable Favorable Genotype 1/4 2/3 Viral load High Low Fibrosis Advanced Mild Gender Male Female Metbolic sd Yes No Steatosis Advanced Mild IL 28Bnon CC CC

  3. Basic factors favorable vs unfavorable for treatment response Unfavorable Favorable Genotype 1/4 2/3 Viral load High Low Fibrosis Advanced Mild Gender Male Female Metbolic sd Yes No Steatosis Advanced Mild IL 28Bnon CC CC HCV kinetics

  4. Viral kinetics during the initial 12 weeks basis for treatment recommendations of today www.mpa.se workshop HCV treatment

  5. Virological response • RVR HCV RNA neg we 4 • EVR minimum 2 log10 decline of HCV RNA at we12 • cEVR HCV RNA neg we 12 • pEVR 2 log10 decline of HCV RNA we 12 but HCV RNA detectable • SlowVR HCV RNApos we 12, neg we 24

  6. RVR and genotype 1/4

  7. SVR according to first neg HCV RNA Genotype 1 % Zeuzem et al J Hepatology 2006

  8. Slow viral response and genotype 1

  9. Slow viral responders effect of prolonging treatment Berg et al Gastroenterology 2006; Sanchez-Tapias et al Gastroenterology 2006; Ferenci et al AASLD 2006

  10. Individualized treatment for naive gt 1 and 4 patients based on viral kinetics • Virological responseTreatment duration • RVR 24*ws • No RVR + cEVR 48 ws (standard) • No RVR + pEVR 72 ws • provided HCV RNA is neg we 24 • No EVR Stop Rx • * In patients lacking negative factors like cirrhosis • Zeuzem et al J Hepatol 2006; Ferenci et al Gastronterology 2009; Sanchez-Tapias et al Gastroenterology 2006, Berg et al Gastroenterology 2006, Jensen et al Hepatology 2006; Pearlman et al Hepatology 2007

  11. Future treatment with SOC + a protease inhibitor will also be based on kinetics

  12. Telaprevirgt 1 naive NS3 serine protease inhibitor

  13. P=0.001 P<0.001 P=0.02 Naive G1 PROVE1 and PROVE2: SVR rates PROVE1 (SVR) PROVE2 (SVR) 100 80 60 Subjects with undetectable HCV RNA (%) 40 20 0 PR48 (control) SVR (n=75) T12/PR24 SVR(n=79) T12/PR48 SVR(n=79) PR48 (control) at12-week follow-up(n=82) T12/PR24 SVR(n=81) McHutchison JG, et al. 43rd EASL 2008, Milan, Italy. 23-27 April 2008. Abstract 4;Zeuzem S, et al. AASLD, San Francisco November 2008

  14. Telaprevir gt 1 experienced

  15. SVR according to rx group

  16. SVR in NR and relapse patients

  17. Telaprevir in gt 2/3 patients?

  18. Study design • Design: Phase IIa multicentre, partially blinded, randomised, stratified for genotype, multiple-dose trial in France, Italy, Sweden and UK TVR (T mono) Peg-IFN + RBV Follow up for  24 weeks after EOT Screening TVR + Peg-IFN + RBV(triple therapy) (T/PR) Peg-IFN + RBV PBO + Peg-IFN + RBV (PR) Peg-IFN + RBV 24 weeks (T mono arm) 22 weeks (T/PR and PR arms) 2 weeks TVR 750 mg q8h; Peg-IFN alfa 2a 180g/week; RBV 800mg/day; EOT = end of treatment; PBO = placebo

  19. Conclusion Telaprevir has only modest effect on gt 2 but no effect on gt 3

  20. ADVANCE: Study design, Phase III trial Genotype1, Naïve Patients Peg-IFN + RBV PR48 (Control) eRVR* YES Peg-IFN + RBV Telaprevir + Peg-IFN + RBV T12/PR24(48) Peg-IFN + RBV NO Peg-IFN + RBV YES Telaprevir+ Peg-IFN + RBV T8/PR24(48) Peg-IFN + RBV NO 0 4 8 12 24 48 Weeks * eRVR = extended RVR, undetectable at weeks 4 and 12 Jacobson I et al, AASLD 2010

  21. Undetectable HCV RNA at Week 4 (RVR) and Weeks 4 and 12 (eRVR) T12PR T8PR PR 100 Patients eligible to receive 24 weeks of total treatment 90 80 68% 66% 70 58% 57% 60 50 % patients with undetectable HCV RNA 40 30 20 9% 8% 10 0 n/N = 246/363 242/364 34/361 212/363 207/364 29/361 Week 4 (RVR) Weeks 4 and 12 (eRVR*) * eRVR = extended RVR, undetectable at weeks 4 and 12 Jacobson I et al, AASLD 2010

  22. SVR Rates by eRVR* Status 97% 100 T12PR T8PR PR 89% 83% 90 80 70 54% 60 50% % patients with SVR 50 39% 40 30 20 10 0 189/212 171/207 28/29 82/151 79/157 130/332 n/N = 48-week regimen 24-week regimen eRVR*+ eRVR*- * eRVR = extended RVR, undetectable at weeks 4 and 12 Jacobson I et al, AASLD 2010

  23. Realize SVR rates press release Sept 7 2010 data based on 662 patients

  24. Boceprevir NS3 serine protease inhibitor

  25. SPRINT-1: Boceprevir + PegIFN/RBV in Treatment-Naive GT1 Patients Sustained Virologic Response* Virologic Breakthrough‡ 100 100 75 80 80 67 56 55 60 60 Proportion of Patients (%) Patients HCV Negative (%) 38 40 40 20 20 12 7 5 4 0 0 0 P/R Control48 Wk P/R/B 28 Wk P/R 4 Wk →P/R/B 24 Wk P/R/B 48 Wk P/R 4 Wk →P/R/B 44 Wk P/R Control 48 Wk P/R/B 28 Wk P/R 4 Wk → P/R/B 24 Wk P/R/B 48 Wk P/R 4 Wk → P/R/B 44 Wk *SVR12 for 48-wk arms and SVR24 for 28-wk arms. ‡Persistent HCV RNA ≥2 log10 increase from nadir and ≥ 50,000 IU/mL. Kwo P, et al. EASL 2009

  26. Boceprevir (Boc) + SOC phase 3 Sprint 2 n=1097 LB4 Poordad et al • A linear protease inhibitor 800 mg t.i.d. • Naïve HCV gt 1 patients 4 week lead in SOC hereafter addition of Boc • Response guided Rx (RGT) if RNA- we 8-24 then 24 weeks others Boc +SOC 48 weeks • Epo use OK given if hemoglobin < 100 g/L • Versus SOC 48 ws

  27. SPRINT 2: Study Design Week 72 Week 4 Week 48 Week 28 Control 48 P/R N = 363 PR lead-in PR + Placebo Follow-up TW 8-24 HCV-RNA Undetectable Follow-up BOC RGT N = 368 PR lead-in PR + Boceprevir TW 8-24 HCV-RNA Detectable Follow-up PR + Placebo BOC/ PR48 N = 366 PR lead-in PR + Boceprevir Follow-up Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight based dosing of 600-1400 mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily

  28. Boceprevir (Boc) + SOC: SVR and Epo use acc. to Rx arm Sprint 2

  29. Boceprevir in relapsers and prior partial NR to SOC Respond 2 abstr 216 Bacon et al

  30. Study Arms and Dosing Regimen Week 36 Week 72 Week 4 Week 48 Control 48 P/R N = 80 PR lead-in PR + Placebo Follow-up TW 8 HCV-RNA Undetectable Week 12 futility Follow-up BOC RGT N = 162 PR lead-in PR + Boceprevir TW 8 HCV-RNA Detectable/ TW 12 Undetectable PR + placebo Follow-up BOC/ PR48 N = 161 PR + Boceprevir PR lead-in Follow-up 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. Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R) using weight based dosing of 600-1400 mg/day in a divided daily dose Boceprevir dose of 800 mg thrice daily

  31. Partial NR

  32. SVR acc. to prior response to SOC Respond 2

  33. Most Common Treatment-Related Adverse Events>15% of patients in any treatment arm

  34. Conclusion Boceprevir Respond 2 Boceprevir increases SVR in relapsers to 70% and partial non-responders to 35 % Many patients develops anaemia and need EPO support

  35. LB5 IL28B (IFN Lambda) polymorfismvs SVR (Thomson AJ et al) 1604/3070 patients from th IDEAL study + 67 others Genotyped for CC, CT and TT

  36. IL28B-related SNPs and HCV(IDEAL Study) rs12979860 (“The Duke SNP”) • Predicts SVR after IFN + ribavirin (Ge et al.) • Predicts clearance after acute HCV (Thomas et al.) • CC favorable, TT unfavorable

  37. Todays treatment is based on kinetics The treatment of tomorrow will aslo be based on kinetics

  38. This year will be a paradigm shift • Addition of a 1stgen protease inhibitor to SOC • Results in 30% higher SVR in naïve HCV genotype 1 patients • Allows shorter treatment schedules for a majority

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