The Future in Hepatitis C Treatment: Therapy Individualization - - PowerPoint PPT Presentation

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The Future in Hepatitis C Treatment: Therapy Individualization - - PowerPoint PPT Presentation

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The Future in Hepatitis C Treatment: Therapy Individualization and STAT-C Dr. med. Christoph Welsch, MD J. W. Goethe-University Hospital Internal Medicine 1 Frankfurt am Main Max-Planck-Institute for Informatics Computational Biology

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SLIDE 1

The Future in Hepatitis C Treatment:

Therapy Individualization and STAT-C

  • Dr. med. Christoph Welsch, MD
  • J. W. Goethe-University

Hospital Internal Medicine 1 Frankfurt am Main Max-Planck-Institute for Informatics Computational Biology & Applied Algorithmics Saarbrücken

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SLIDE 2

Standard-of-Care and Treatment Individualization

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SLIDE 3
  • 170 Mill. people

worldwide chronically infected with HCV

  • Recommended

treatment is a 48-week course

  • f PegIFN

plus ribavirin (standard-of-care, SOC)

  • Treatment often

poorly tolerated, many side effects

  • Overall sustained

response rates are low, 40 to 50% in HCV genotype 1

  • Many

patients will not be cured by current SOC

  • Patients
  • f European ancestry

have a significant higher probability

  • f being

cured than patients

  • f African ancestry
  • Identification
  • f the

determinants

  • f response

to treatment is a high priority

Chronic Hepatitis C (CHC)

Green et al., Gastroenterology 2002 Ge et al., Nature 2009

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SLIDE 4

Standard-of-Care (SOC) in Chronic Hepatitis C

Sarrazin, Berg et al., Z Gastroenterol 2009

  • SOC in CHC consists
  • f a 48-week course
  • f pegylated

interferon-alpha (PegIFN-2a or

  • 2b) plus ribavirin
  • IFN-monotherapy
  • nly

in case

  • f ribavirin

contraindications (e.g. previous hemolysis)

  • Ribavirin

dosing according to body weight

  • Treatment duration

depends

  • n HCV genotype, pre-

treatment viral load (HCV-RNA), treatment response (viral kinetics)

  • Specific

criteria have been defined for treatment interruption incase

  • f non-response
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SLIDE 5

Dependency

  • f treatment

duration

  • n HCV-RNA decay

16/24 48 72

4 6 2 5

HCV-RNA (log10 IU/ml)

W24 3 1 W20 W16 W12 W8 W4

rapid-responder (RVR) standard-responder (cEVR) slow-responder HCV-RNA negative HCV-RNA negative

Individualized Treatment Duration

Sarrazin, Berg et al., Z Gastroenterol 2009

weeks

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SLIDE 6

Parameter OR

  • HCV Genotype 2 or

3 3,3-6,0

  • Normal GGT (< 0,95-fold ULN)

5,7

  • Low pre-treatment

HCV-RNA level (<8x105 IU/ml) 1,9-2,9

  • High GPT/ALT (> 3-fold ULN)

1,8

  • Mild liver

fibrosis 1,6

  • Age <40 yr

(duration

  • f chronic

infection?) 1,4

  • Compliance

1,8

  • Sex (female)

1,5

Therapy in Chronic Hepatitis C

Predictive Parameters for Sustained-Virological Response (SVR)

Poynard et al., Lancet 1998 Poynard et al., Hepatology 2000 Manns et al., Lancet 2001 Fried et al., NEJM 2003 Berg et al., Hepatology 2003 Hadziyannis et al., Ann Intern Med 2004

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SLIDE 7

IL28B polymorphism

Chromosome 19

Contributes to viral resistance Upregulated due to IFN Upregulated in RNA-virus infection

Therapy in Chronic Hepatitis C

Novel Predictive Parameter for Treatment Response

Ge et al., Nature 2009

  • Genome-wide

association study GWAS

  • A total of 1.671 treatment-naive

individuals were genotyped

  • Search

for determinants

  • f

treatment response

  • Genetic

polymorphisms near the IL28B gene

  • Encoding

interferon-lambda-3

  • Associated

with

  • app. 2-fold

change to treatment response

  • Both

in patients

  • f European

ancestry, as well as African

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SLIDE 8

Therapy in Chronic Hepatitis C

Novel Predictive Parameter for Treatment Response

Ge et al., Nature 2009 Suppiah et al., Nat Genetics 2009 Tanaka et al., Nat Genetics 2009 Thomas et al., Nature 2009 Thompson et al., Gastroenterology 2010

  • Better

response genotype C shows higher allele frequency in European than African ancestry

  • Lower

IL28B expression in individuals carrying the minor alleles

  • Association with

SVR rates

  • C/C genotype

strongly enhances resolution

  • f HCV infection

and spontaneous clearence

  • C/C genotype

strongly associated with improved early viral kinetics and RVR in Caucasians

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SLIDE 9

The Era

  • f Direct

Antiviral Agents (DAAs)

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SLIDE 10

Molecular Target Structures for STAT-C

NS3.4A Serine Protease NS5B RNA-Polymerase

  • NS2/3 Cysteine

Protease Polyprotein processing

  • NS3.4A Serine

Protease Polyprotein processing, viral replication, innate immunity

  • NS3 Helicase/Nukleosidtriphosphatase
  • NS4A
  • NS5A Subdomane

I Viral replication, IFN-resistance

  • NS5B RNA-dependent

RNA-Polymerase Viral replication

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SLIDE 11

Antiviral Activity

  • f Different DAAs

Comparison of Different Drug Classes

Sarrazin and Zeuzem, Gastroenterology 2010

  • DAAs

inhibit viral replication

  • DAAs

are in phase 1, 2 and 3 trials

  • Compounds

targeting the NS3.4A protease, NS5B RNA polymerase, NS5A and host cell factors involved in viral replication

  • Monotherapy

pose a high risk

  • f

resistance development due to high genetic heretogeneity and rapid viral replication

Antiviral activities

Mean

  • r

median maximum decrease in HCV-RNA log10 IU/mL, determined from phase 1 monotherapy studies (3 to14 days) in HCV genotype 1

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SLIDE 12

NS3.4A Serine Protease

Structure and Function

Lorenz et al., Nature 2006 Kronenberger et al., Clin Liver Dis 2008

STRUKTURE and FUNCTION

  • NS3 Protease Domane

(aa 1-181)

  • Serine Protease
  • Chymotrypsine-like fold
  • Polyprotein

processing

  • Active site “catalytic triad”

(H57, D81, S139)

  • Oxyanion

hole (G137)

  • Zinc-finger (C97, C99, C145)
  • H147
  • NS4A

active site “catalytic triad” zinc-finger NS4A subdomain boundary

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SLIDE 13

NS3.4A Serine Protease

Targeting

Sarrazin et al., Gastroenterology 2007 Kronenberger, Welsch et al., Clin Liver Dis 2008

TARGETING

  • Substrate-

and product analogs

  • Peptidomimetics

(SCH 503034, VX-950)

  • tri-Peptides
  • Serine-trap

inhibitors

  • Makrozyclic

inhibitors

(e.g. ITMN-191)

  • NS4A inhibitors

(e.g. ACH-806, ACH-1095)

WT WT WT V36M/L/A T54S R155K/M/S/T A156S 1a 1b T54A A156T/V 10 100 Enzyme IC50 [nM] 1000 10000 100000 Resistance mutations Resistance mutations

Telaprevir

VX-950

active site “catalytic triad” zinc-finger NS4A subdomain boundary V36 T54 R155 A156

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SLIDE 14

Peptidomimetics and Resistance Mutations

N N O O O N N O O N N N O

N N O O O N O N N O

Telaprevir

VX-950

Boceprevir

SCH 503034

P’1

P1 P3 P2 P4 P1 P3 P2 P4

RESISTENCE MUTATIONS

  • 3 to 4 days

(during monotherapy)

  • Low/medium

level

(V36, T54, R155)

  • High level

(A156)

  • Long-term

resistance

e.g. Boceprevir (1 to 4 years)

  • Cross-resistance

Peptidomimetics mimic the natural substrate

  • f the

protease Side chain modification for specificity and efficacy (e.g. P‘1 site)

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SLIDE 15

Resistance in STAT-C and Therapy Optimization

  • Classification
  • f drugs

and their chemical groups (e.g. specific side chains)

  • Characterization
  • f molecular

resistance mechanisms

  • Assign

mutants to corresponding molecular resistance mechanisms and associated drugs/chemical groups

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SLIDE 16

Resistance in STAT-C and Therapy Optimization

  • Classification
  • f drugs

and their chemical groups (e.g. specific side chains)

  • Characterization
  • f molecular

resistance mechanisms

  • Assign

mutants to corresponding molecular resistance mechanisms and associated drugs/chemical groups

  • Identification
  • f potential cross-resistance
  • Prediction
  • f primary/secundary

treatment failure

  • Optimized

drug combinations for STAT-C

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SLIDE 17

Binding Mode in Peptidomimetics

Welsch, Domingues et al., Genome Biology 2008 Domingues et al., Bioinformatics 2007; http://struster.bioinf.mpi-inf.mpg.de/

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SLIDE 18

Residue Interaction Network for Molecular Resistance Analysis

Welsch, Domingues et al. Genome Biology 2008 Susser, Welsch et al., Hepatology 2009

HCV-NS3.4A Protease, PDB entry: 1RTL

edges: H-bonds, van der Waals interactions nodes: amino acids

N N O O O N O N N O

Boceprevir

SCH 503034

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SLIDE 19

Topology

  • f Resistance

Mutations

Welsch, Domingues et al., Genome Biology 2008 Susser et al., Hepatology 2009 Telaprevir (VX-950) cyclopropyl group Telaprevir (VX-950) cyclopropyl group

T54 T54 T54 T54 V36 V36 V36 V36

NS3.4A Serine Protease

side view

NS3.4A Serine Protease

top view

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SLIDE 20

Telaprevir Resistance due to V36 Polymorphisms

Welsch, Domingues et al., Genome Biology 2008 Hartmann et al., Protein Science 2007, http://irecs.bioinf.mpi-inf.mpg.de/

  • Orientation
  • f amino

acid side chains in the wildtype V36 and polymorphisms MLAG

  • van der Waals

interactions between residue V36 and F43

cyclopropyl group surface patch F43 V36 M/L/A/G Cγ Cα Cβ Cγ

  • V36

V36 F43 F43 S139 S139 Q41 Q41

PDB entry: 1RTL

V36 V36 F43 F43

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SLIDE 21

Telaprevir Resistance due to V36 Polymorphisms

Welsch, Domingues et al., Genome Biology 2008 Hartmann et al., Protein Science 2007, http://irecs.bioinf.mpi-inf.mpg.de/

  • Orientation
  • f amino

acid side chains in the wildtype V36 and polymorphisms MLAG

  • van der Waals

interactions between residue V36 and F43

  • Loss
  • f 2nd

Cgamma for all V36 polymorphisms

  • bserved
  • Consecutive

change in the cyclopropyl-binding pocket

cyclopropyl group surface patch F43 V36 M/L/A/G Cγ Cα Cβ Cγ

  • V36

V36 F43 F43 S139 S139 Q41 Q41

PDB entry: 1RTL

V36 V36 F43 F43

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SLIDE 22

Compound Specificity

  • f V36 Polymorphisms

Welsch, Domingues et al., Genome Biol 2008 F43 F43 V36 V36 cyclopropyl P1 ’ cyclopropyl P1 ’

N N O O O N N O O N N N O N N O O O N O N N O

Telaprevir

VX-950

Boceprevir

SCH 503034

20 40 60 80 100 120 0µM 0,15µM 5µM 10µM 20µM 30µM 120 100 80 60 40 20 0μM 0,15μM 5μM 10μM 20μM 30μM 20 40 60 80 100 120 0µM 0,15µM 5µM 10µM 20µM 30µM 120 100 80 60 40 20 0μM 0,35μM 1μM 5μM 10μM 30μM

HCV-RNA [%]

Boceprevir [µM] Telaprevir [µM] WT V36G

IC50

WT V36G IC50

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SLIDE 23

Results

  • f the

PROVE 2-Trial

Hezode, Forestier et al., NEJM 2009

20 40 60 80 100

12 (triple) + 12 (SOC)

TVR+PEG2a+Riba →PEG2a+Riba

48 (SOC)

PEG2a+Riba

12 (triple)

TVR+PEG2a+Riba SVR rate (%)

Telaprevir + PEG2a/Ribavirin vs. standard-of-care (SOC)

cEVR TW24 RVR SVR cEVR RVR SVR cEVR TW24 RVR SVR

80 43 73 80 69 69 13 59 70 60 46

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SLIDE 24

Approval

  • f First DAAs
  • Boceprevir

(BOC, SCH503034)

  • Phase 3 clinical

trial

  • Combination

therapy with PEG-2b and ribavirin

  • Therapy

duration 28 to 48 weeks

  • Genotype 1, naiv, relapser, non-responder
  • Telaprevir

(TVR, VX-950)

  • Phase 3 clinical

trial

  • Combination

therapy with PEG-2a and ribavirin

  • Therapy

duration 24 to 48 weeks

  • Genotype 1, naiv, relapser, non-responder

Phase 3 trial ending summer/autumn 2010 Drug approval expected 2011/2012

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SLIDE 25

The Future in Hepatitis C Treatment:

Therapy Individualization and STAT-C

  • Dr. med. Christoph Welsch, MD
  • J. W. Goethe-University

Hospital Internal Medicine 1 Frankfurt am Main Max-Planck-Institute for Informatics Computational Biology & Applied Algorithmics Saarbrücken