What is to be expected from new antivirals against Hepatitis C? A - PowerPoint PPT Presentation

What is to be expected from new antivirals against Hepatitis C? A clinician‘s perspective. 22.04.2010 Arevir-Meeting, Bonn Michael Biermer Medizinische Klinik mit Schwerpunkt Gastroenterologie und Hepatologie Charité Campus Virchow Klinikum, Berlin, Germany

Treatment Outcome – chronic Hepatitis C Sustained virological response = SVR Relapse Nonresponse Break-through 8 HCV RNA log iU/ml 7 6 5 4 3 2 1 Limit of detection HCV-RNA 0 4 Weeks 12 24 48 72 Peginterferon-alpha Ribavirin

Treatment Outcome – chronic Hepatitis C Sustained virological response = SVR Relapse Nonresponse 8 HCV RNA log iU/ml 7 6 5 4 3 2 1 Limit of detection HCV-RNA 0 4 Weeks 12 24 48 72 Peginterferon-alpha Ribavirin

Treatment Outcome – chronic Hepatitis C SVR 55 % Relapse 20 % GT 1 Nonresponse 25 % 8 HCV RNA log iU/ml 7 6 5 4 3 2 1 Limit of detection HCV-RNA 0 4 Weeks 12 24 48 72 Peginterferon-alpha Ribavirin

Hepatitis C – treatment regimens of the future Higher SVR-rate? Shorter treatment duration? Better safety / tolerability profile? New options for treatment failures? Extended pool of treatment candidates?

Prediction of a negative treatment outcome Host factors Viral factors adipositas viral Genotype insulin resistance 1 > 4 > 3 > 2 high degree of fibrosis advanced age high viral load at baseline long course of infection > 400.000 IU/ml race: black > caucasian > asian IL28B Genotype: TT > TC > CC

Prediction of a negative treatment outcome Host factors Viral factors adipositas viral Genotype insulin resistance 1 > 4 > 3 > 2 high degree of fibrosis advanced age high viral load at baseline long course of infection > 400.000 IU/ml race: black > caucasian > asian IL28B Genotype: TT > TC > CC

Response giuded Therapy Treatment duration tailored in response to the time needed to reach complete viral suppression negative! 4 24 6 36 8 42 12 48 24 72 First time negative at week Treatment duration in weeks

Treatment Outcome – chronic Hepatitis C Sustained virological response = SVR Relapse Nonresponse 8 HCV RNA log iU/ml 7 6 5 4 3 2 1 Limit of detection HCV-RNA 0 4 Weeks 12 24 48 72 Peginterferon-alpha Ribavirin

Treatment Outcome – chronic Hepatitis C Sustained virological response = SVR Relapse Nonresponse 8 HCV RNA log iU/ml 7 6 5 4 3 2 1 Limit of detection HCV-RNA 0 4 Weeks 12 24 48 72 Peginterferon-alpha Ribavirin

HCV Protease Inhibitor - BILN 2061 Phase 1 BILN 2061 BILN 2061 10,00,000 Placebo Placebo ) mL) 1,000,000 HCV RNA (IU/mL HCV RNA (IU/ 100,000 BILN 2061 Rx BILN 2061 Rx Placebo Placebo 10,000 10,000 Tx- -naive naive Tx Nonresponders Nonresponders n=12 n=12 1,000 0 2 4 6 8 Days Hinrichsen H, et al. Gastroenterology. 2004;127:1347

HCV-Proteins – Targets for DAA 3 C E1 E2 p7 2 3 4A 4B 5A 5B NS3-Protease Metallo-/ Cofaktor Cysteinprotease RNA-dependend Capsid Envelope- Serin- NTPase/ RNA-Polymerase glycoproteins protease Helicase

HCV-Proteins – Targets for DAA X 3 C E1 E2 p7 2 3 4A 4B 5A 5B NS3-Protease Metallo-/ Cofaktor Cysteinprotease RNA-dependend Capsid Envelope- Serin- NTPase/ RNA-Polymerase glycoproteins protease Helicase

Compounds in Development Sarrazin C., Zeuzem S. Gastroenterology 2010

Compounds in Development Protease-Inhibitors Polymerase-Inhibitors (nuc) Polymerase-Inhibitors (non-nuc) NS5A-Inhibitors Others Sarrazin C., Zeuzem S. Gastroenterology 2010

Compounds in Development Approval (Europe) 2012? Sarrazin C., Zeuzem S. Gastroenterology 2010

Prove 2 Study – Phase II PEG-Interferon α 2a Telaprevir Ribavirin A B C D 0 12 24 48 Hézode C et al. NEJM 2009

Prove 2 Study – Mean HCV-RNA Reduction Hézode C et al. NEJM 2009

Prove 2 Study – SVR Rate PEG-Interferon α 2a SVR in % Telaprevir Ribavirin 46 A B 69 C 60 D 36 0 12 24 48 Hézode C et al. NEJM 2009

Functional Monotherapy – Break Through Jacobsen I. et al. AASLD 2007

PROVE 3: SVR Rates of GT1 patients with Nonresponse or Relapse/BT to prior treatment (N=453) Wk 12 Wk 24 Wk 36 Wk 48 24-wk TVR + SOC* SOC* (n = 114) follow-up TVR + SOC* SOC* (n = 115) 24-wk † TVR + Peg-IFNa (no RBV) (n = 113) follow-up Standard of Care (SOC)* (n = 111) *SOC (standard of care): PEG-IFN 180 µg qwk + RBV 1000–1200 mg/d. McHutchison JG et al. NEJM 2010; Manns M et al. EASL 09. Abstr 1044.

PROVE 3: SVR Rates of GT1 patients with Nonresponse or Relapse/BT to prior treatment (N=453) SVR Rates Prior Prior Nonresponse Relapse/BT Wk 12 Wk 24 Wk 36 Wk 48 24-wk TVR + SOC* 39% 69% SOC* (n = 114) follow-up TVR + SOC* 38% 76% SOC* (n = 115) 24-wk † TVR + Peg-IFNa (no RBV) 10% 42% (n = 113) follow-up Standard of Care (SOC)* 9% 20% (n = 111) *SOC (standard of care): PEG-IFN 180 µg qwk + RBV 1000–1200 mg/d. McHutchison JG et al. NEJM 2010; Manns M et al. EASL 09. Abstr 1044.

Telaprevir Treatment Failures SVR Failure Prove 2 – treatment naive 69 % 31 % Prove 3 – prior relapse / BT 76 % 24 % Prove 3 – prior nonresponse 39 % 61 %

Telaprevir Treatment Failures SVR Failure Prove 2 – treatment naive 69 % 31 % Prove 3 – prior relapse / BT 76 % 24 % Prove 3 – prior nonresponse 39 % 61 %

HCV mutations in response to Telaprevir treatment Sarrazin et al. Gastorenterol. 2007;132:1767-77

HCV mutations in response to Telaprevir treatment 4 years follow-up: 27 patients 13 lost to FU 14 patients 4 SVR after re-treatment 10 patients 1 V36 M/A 9 wild-type Susser S. et al. EASL 2010

HCV mutations in response to Telaprevir treatment Susser S. et al. Hepatology 2009;50:1709-18

Resistance mutations in response to DAA Mutations in response to Protease-Inhibitor treatment Sarrazin C., Zeuzem S. Gastroenterology 2010

Interferon-free treatment? X Protease-Inhinbitor Monotherapy Mutations in response to Protease-Inhibitors X Protease-Inhibitor Combination

Resistance mutations in response to DAA Mutations in response to Protease-Inhibitors V 36 A / M T 54 S / A V 55 A Q 80 R / K R 155 K / T / Q A 156 S A 156 T / V D 168 A / V / T / H V 170 A / T Mutations in response to Polymerase-Inhibitors P 496 A / S S 96 T V 499 A S 282 T G 554 D C 316 V / N D 559 G S 365 T / A M 414 T / L L 419 M / N Y 448 C / H I 482 L / V / T V 494 I / A P 495 S / L / A / T Sarrazin C., Zeuzem S. Gastroenterology 2010

Interferon-free treatment? Combination Protease-Inhibitor Polymerase-Inhibitor ? Several studies planned

NS4A Inhibition: BMS 790052 Phase IIa % HCV-RNA negative 48 weeks of PegInterferon-a2a 180 µg/week + Ribavirin 1000 – 1200 mg/d + BMS790052 3 mg, 10 mg, 60 mg or placebo (1:1:1:1) Pol S. et al. EASL 2010

HCV-Proteins – Targets for DAA X X X 3 C E1 E2 p7 2 3 4A 4B 5A 5B NS3-Protease Metallo-/ Cofaktor Cysteinprotease RNA-dependend Capsid Envelope- Serin- NTPase/ RNA-Polymerase glycoproteins protease Helicase

PegInf-a2b and Ribavirin +/- Vitamin D 100 96% 80 86% 60 % Vit D + 48% 40 Vit D - 41% 20 0 EVR SVR n=27 n=31 n=15 n=12 48 weeks of PegInterferon-a2b 1,5µg/kg/w + Ribavirin 1000 – 1200 mg/d +/- Vitamin D 1000 – 4000 IU/d Abu Mouch et al. EASL 2010 #

„Index-Patient“ – Re-Treatment with PI-Triple Therapy Silibinin 1400 mg i.v. Silibinin 1400 mg i.v. 8 HCV RNA log iU/ml 8.680.000 7 6 236.000 5 25.000 4 4.730 1190 751 484 3 460 176 2 145 98 SVR 1 Week 0 1 2 3 4 5 6 7 48 72 PegInterferon a-2a 180 µg/Woche Ribavirin 1000 mg/d Protease-Inhibitor Biermer M. et al. EASL 2010

Treatment options in the future Easy to treat patient Difficult to treat patient young nonresponse no fibrosis cirrhosis 280.000 IU/ml 2.800.000 IU/ml IL28B GT: CC IL28B GT: TT

Treatment options in the future Easy to treat patient Difficult to treat patient 48 weeks of 12 weeks of PegInterferon alpha Protease-Inhibitor PegInterferon alpha Ribavirin Ribavirin Vitamin D Protease-Inhibitor 24 w 12 weeks of (Polymerase-Inhibitor 12 w) Protease-Inhibitor (5 Silibinin-Infusions) Polymerase-Inhibitor (Ribavirin)

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