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. Michael Biermer

Medizinische Klinik mit Schwerpunkt Gastroenterologie und Hepatologie Charité Campus Virchow Klinikum, Berlin, Germany

22.04.2010 Arevir-Meeting, Bonn

Treatment Outcome – chronic Hepatitis C

HCV RNA log iU/ml

1 2 3 4 5 6 7 8 4 12 24 48 72 Weeks

Limit of detection HCV-RNA

Sustained virological response = SVR Relapse Nonresponse

Ribavirin Peginterferon-alpha

Break-through

Treatment Outcome – chronic Hepatitis C

HCV RNA log iU/ml

1 2 3 4 5 6 7 8 4 12 24 48 72 Weeks

Limit of detection HCV-RNA

Sustained virological response = SVR Relapse Nonresponse

Ribavirin Peginterferon-alpha

Treatment Outcome – chronic Hepatitis C

HCV RNA log iU/ml

1 2 3 4 5 6 7 8 4 12 24 48 72 Weeks

Limit of detection HCV-RNA

SVR Relapse Nonresponse

Ribavirin Peginterferon-alpha

25 % 20 % 55 % GT 1

Hepatitis C – treatment regimens of the future

Higher SVR-rate? Shorter treatment duration? Better safety / tolerability profile? Extended pool of treatment candidates? New options for treatment failures?

adipositas

Prediction of a negative treatment outcome

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

adipositas

Prediction of a negative treatment outcome

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

Treatment duration tailored in response to the

First time negative at week Treatment duration in weeks 4 6 8 12 24 24 36 42 48 72

Response giuded Therapy

negative!

time needed to reach complete viral suppression

Treatment Outcome – chronic Hepatitis C

HCV RNA log iU/ml

1 2 3 4 5 6 7 8 4 12 24 48 72 Weeks

Limit of detection HCV-RNA

Sustained virological response = SVR Relapse Nonresponse

Ribavirin Peginterferon-alpha

Treatment Outcome – chronic Hepatitis C

HCV RNA log iU/ml

1 2 3 4 5 6 7 8 4 12 24 48 72 Weeks

Limit of detection HCV-RNA

Sustained virological response = SVR Relapse Nonresponse

Ribavirin Peginterferon-alpha

BILN 2061 BILN 2061 10,00,000 1,000,000 100,000 10,000 10,000 1,000 2 4 6 8

Days

HCV RNA (IU/ HCV RNA (IU/mL mL) )

Nonresponders Nonresponders BILN 2061 Rx BILN 2061 Rx Placebo Placebo Tx Tx-

• naive

naive

Placebo Placebo Hinrichsen H, et al. Gastroenterology. 2004;127:1347

Phase 1

HCV Protease Inhibitor - BILN 2061

n=12 n=12

C E1 E2 p7 2 3 5B 5A 4B

3 Capsid Envelope- glycoproteins Metallo-/ Cysteinprotease NTPase/ Helicase NS3-Protease Cofaktor RNA-dependend RNA-Polymerase Serin- protease

4A

HCV-Proteins – Targets for DAA

C E1 E2 p7 2 3 5B 5A 4B

3 Capsid Envelope- glycoproteins Metallo-/ Cysteinprotease NTPase/ Helicase NS3-Protease Cofaktor RNA-dependend RNA-Polymerase Serin- protease

4A

HCV-Proteins – Targets for DAA

X

Compounds in Development

Sarrazin C., Zeuzem S. Gastroenterology 2010

Compounds in Development

Sarrazin C., Zeuzem S. Gastroenterology 2010

Protease-Inhibitors Polymerase-Inhibitors (nuc) Polymerase-Inhibitors (non-nuc) Others NS5A-Inhibitors

Compounds in Development

Sarrazin C., Zeuzem S. Gastroenterology 2010

Approval (Europe) 2012?

Telaprevir PEG-Interferon α 2a

A B C D

Ribavirin

48 12 24 Hézode C et al. NEJM 2009

Prove 2 Study – Phase II

Prove 2 Study – Mean HCV-RNA Reduction

Hézode C et al. NEJM 2009

Prove 2 Study – SVR Rate

Telaprevir PEG-Interferon α 2a

A B C D

Ribavirin

48 12 24

SVR in %

46 69 60 36

Hézode C et al. NEJM 2009

Functional Monotherapy – Break Through

Jacobsen I. et al. AASLD 2007

*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)

TVR + SOC* (n = 114) SOC* TVR + SOC* (n = 115) TVR + Peg-IFNa (no RBV) (n = 113) SOC* Wk 12 Wk 24 Wk 48 24-wk† follow-up Wk 36 Standard of Care (SOC)* (n = 111) 24-wk follow-up

*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.

SVR Rates Prior Nonresponse Prior Relapse/BT

39% 69% 38% 76% 10% 42% 9% 20%

TVR + SOC* (n = 114) SOC* TVR + SOC* (n = 115) TVR + Peg-IFNa (no RBV) (n = 113) SOC* Wk 12 Wk 24 Wk 48 24-wk† follow-up Wk 36 Standard of Care (SOC)* (n = 111) 24-wk follow-up

PROVE 3: SVR Rates of GT1 patients with Nonresponse or Relapse/BT to prior treatment (N=453)

Telaprevir Treatment Failures

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

Telaprevir Treatment Failures

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

Sarrazin et al. Gastorenterol. 2007;132:1767-77

HCV mutations in response to Telaprevir treatment

HCV mutations in response to Telaprevir treatment

Susser S. et al. EASL 2010

4 years follow-up: 27 patients 13 lost to FU 4 SVR after re-treatment 9 wild-type 1 V36 M/A 14 patients 10 patients

Susser S. et al. Hepatology 2009;50:1709-18

HCV mutations in response to Telaprevir treatment

Resistance mutations in response to DAA

Sarrazin C., Zeuzem S. Gastroenterology 2010

Mutations in response to Protease-Inhibitor treatment

Interferon-free treatment?

Mutations in response to Protease-Inhibitors

Protease-Inhibitor Combination Protease-Inhinbitor Monotherapy

X X

Resistance mutations in response to DAA

Sarrazin C., Zeuzem S. Gastroenterology 2010

Mutations in response to Protease-Inhibitors Mutations in response to Polymerase-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 S 96 T S 282 T C 316 V / N 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 P 496 A / S V 499 A G 554 D D 559 G

Interferon-free treatment?

Protease-Inhibitor

?

Combination Polymerase-Inhibitor Several studies planned

NS4A Inhibition: BMS 790052 Phase IIa

Pol S. et al. EASL 2010 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)

% HCV-RNA negative

C E1 E2 p7 2 3 5B 5A 4B

3 Capsid Envelope- glycoproteins Metallo-/ Cysteinprotease NTPase/ Helicase NS3-Protease Cofaktor RNA-dependend RNA-Polymerase Serin- protease

4A

HCV-Proteins – Targets for DAA

X X X

PegInf-a2b and Ribavirin +/- Vitamin D

20 40 60 80 100 EVR SVR Vit D + Vit D -

Abu Mouch et al. EASL 2010 #

86% 96% 41% 48% %

48 weeks of PegInterferon-a2b 1,5µg/kg/w + Ribavirin 1000 – 1200 mg/d +/- Vitamin D 1000 – 4000 IU/d n=27 n=31 n=15 n=12

HCV RNA log iU/ml

2 4 1 2 3 4 5 6 7 8

PegInterferon a-2a 180 µg/Woche Ribavirin 1000 mg/d

1 3 6 5

Protease-Inhibitor

7 8.680.000 236.000 25.000 4.730 1190 751 460 176 98 145 484 SVR Week

Silibinin 1400 mg i.v. Silibinin 1400 mg i.v.

48 72

„Index-Patient“ – Re-Treatment with PI-Triple Therapy

Biermer M. et al. EASL 2010

Treatment options in the future

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

Treatment options in the future

Easy to treat patient Difficult to treat patient

Ribavirin PegInterferon alpha Protease-Inhibitor 12 weeks of Protease-Inhibitor 24 w Ribavirin PegInterferon alpha 48 weeks of (Polymerase-Inhibitor 12 w) (5 Silibinin-Infusions) (Ribavirin) Polymerase-Inhibitor Protease-Inhibitor 12 weeks of Vitamin D

Thank you