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

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

Standard-of-Care and Treatment Individualization

Chronic Hepatitis C (CHC)  170 Mill. people worldwide chronically infected with HCV of PegIFN   Recommended treatment is a 48-week course 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 of European ancestry have a significant higher probability of being cured than patients of African ancestry  Identification of the determinants of response to treatment is a high priority Green et al., Gastroenterology 2002 Ge et al., Nature 2009

Standard-of-Care (SOC) in Chronic Hepatitis C  SOC in CHC consists of a 48-week course of pegylated (PegIFN  -2a or interferon-alpha -2b) plus ribavirin IFN-monotherapy only in case of ribavirin contraindications  (e.g. previous hemolysis)  Ribavirin dosing according to body weight  Treatment duration depends on HCV genotype, pre- treatment viral load (HCV-RNA), treatment response (viral kinetics)  Specific criteria have been defined for treatment interruption incase of non-response Sarrazin, Berg et al., Z Gastroenterol 2009

Individualized Treatment Duration Dependency of treatment duration on HCV-RNA decay HCV-RNA 6 (log 10 IU/ml) rapid-responder (RVR) 5 standard-responder (cEVR) slow-responder 4 HCV-RNA HCV-RNA negative negative 3 2 1 0 0 W4 W8 W12 W20 W24 W16 weeks 16/24 48 72 Sarrazin, Berg et al., Z Gastroenterol 2009

Therapy in Chronic Hepatitis C Predictive Parameters for Sustained-Virological Response (SVR) 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 (<8x10 5 IU/ml) 1,9-2,9   High GPT/ALT (> 3-fold ULN) 1,8  Mild liver fibrosis 1,6  Age <40 yr (duration of chronic infection?) 1,4  Compliance 1,8  Sex (female) 1,5 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

Therapy in Chronic Hepatitis C Novel Predictive Parameter for Treatment Response IL28B polymorphism  Genome-wide association study Chromosome 19 GWAS Contributes to viral resistance Upregulated due to IFN  A total of 1.671 treatment-naive Upregulated in RNA-virus infection individuals were genotyped  Search for determinants of treatment response  Genetic polymorphisms near the IL28B gene  Encoding interferon-lambda-3  Associated with app. 2-fold change to treatment response  Both in patients of European ancestry, as well as African Ge et al., Nature 2009

Therapy in Chronic Hepatitis C Novel Predictive Parameter for Treatment Response 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 of HCV infection and spontaneous clearence C/C genotype strongly associated  with improved early viral kinetics and RVR in Caucasians 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

The Era of Direct Antiviral Agents (DAAs)

Molecular Target Structures for STAT-C NS3.4A Serine Protease  NS2/3 Cysteine Protease Polyprotein processing NS5B RNA-Polymerase  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

Antiviral Activity of Different DAAs Comparison of Different Drug Classes 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 of  resistance development due to Antiviral activities high genetic heretogeneity and rapid viral replication Mean or median maximum decrease in HCV-RNA log10 IU/mL, determined from phase 1 monotherapy studies (3 to14 days) in HCV genotype 1 Sarrazin and Zeuzem, Gastroenterology 2010

NS3.4A Serine Protease Structure and Function active site “catalytic triad” NS4A STRUKTURE and FUNCTION  NS3 Protease Domane (aa 1-181)  Serine Protease  Chymotrypsine-like fold  Polyprotein processing  Active site “catalytic triad” (H57, D81, S139) subdomain boundary  Oxyanion hole (G137)  Zinc-finger (C97, C99, C145) zinc-finger  H147  NS4A Lorenz et al., Nature 2006 Kronenberger et al., Clin Liver Dis 2008

NS3.4A Serine Protease Enzyme IC 50 [nM ] Targeting 100000 A156T/V Resistance Resistance WT WT WT mutations mutations 10000 A156S T54A 1000 1b T54S R155K/M/S/T 100 V36M/L/A 1a active site “catalytic triad” NS4A 10 Telaprevir VX-950 T54 TARGETING V36  Substrate- and product analogs R155 A156  Peptidomimetics (SCH 503034, VX-950)  tri-Peptides  Serine-trap inhibitors subdomain boundary  Makrozyclic inhibitors (e.g. ITMN-191) zinc-finger  NS4A inhibitors (e.g. ACH-806, ACH-1095) Sarrazin et al., Gastroenterology 2007 Kronenberger, Welsch et al., Clin Liver Dis 2008

Peptidomimetics and Resistance Mutations RESISTENCE MUTATIONS Telaprevir VX-950  3 to 4 days (during monotherapy) P 2  Low/medium level (V36, T54, R155) O N N  High level O N (A156) N N O O  Long-term resistance N P’ 1 O e.g. Boceprevir (1 to 4 years) O N P 4 P 3 P 1  Cross-resistance Boceprevir SCH 503034 O P 2 N N N N N O O O O P 4 P 3 P 1 Peptidomimetics mimic the natural substrate of the protease Side chain modification for specificity and efficacy (e.g. P‘ 1 site)

Resistance in STAT-C and Therapy Optimization  Classification of drugs and their chemical groups (e.g. specific side chains)  Characterization of molecular resistance mechanisms  Assign mutants to corresponding molecular resistance mechanisms and associated drugs/chemical groups

Resistance in STAT-C and Therapy Optimization Classification of drugs and their chemical groups  (e.g. specific side chains)  Characterization of molecular resistance mechanisms  Assign mutants to corresponding molecular resistance mechanisms and associated drugs/chemical groups  Identification of potential cross-resistance  Prediction of primary/secundary treatment failure  Optimized drug combinations for STAT-C

Binding Mode in Peptidomimetics Welsch, Domingues et al., Genome Biology 2008 Domingues et al., Bioinformatic s 2007; http://struster.bioinf.mpi-inf.mpg.de/

Residue Interaction Network for Molecular Resistance Analysis HCV-NS3.4A Protease, PDB entry: 1RTL edges: H-bonds, van der Waals interactions nodes: amino acids O N N N N N O O O O Boceprevir SCH 503034 Welsch, Domingues et al. Genome Biology 2008 Susser, Welsch et al., Hepatology 2009

Topology of Resistance Mutations Telaprevir (VX-950) Telaprevir (VX-950) cyclopropyl group cyclopropyl group V36 V36 T54 T54 V36 V36 T54 T54 NS3.4A Serine Protease NS3.4A Serine Protease top view side view Welsch, Domingues et al., Genome Biology 2008 Susser et al., Hepatology 2009

Telaprevir Resistance due to V36 Polymorphisms ● Q41 Q41 F43 ● F43 F43 V36 V36 V36 M/L/A/G surface patch C γ C β ● cyclopropyl group C γ C α F43 V36 F43 V36 S139 PDB entry: 1RTL S139  Orientation of amino acid side chains in the wildtype V36 and polymorphisms MLAG  van der Waals interactions between residue V36 and F43 Welsch, Domingues et al., Genome Biology 2008 Hartmann et al., Protein Science 2007, http://irecs.bioinf.mpi-inf.mpg.de/

Telaprevir Resistance due to V36 Polymorphisms ● Q41 Q41 F43 ● F43 F43 V36 V36 V36 M/L/A/G surface patch C γ C β ● cyclopropyl group C γ C α F43 V36 F43 V36 S139 PDB entry: 1RTL S139  Orientation of amino acid side chains in the wildtype V36 and polymorphisms MLAG  van der Waals interactions between residue V36 and F43  Loss of 2 nd Cgamma for all V36 polymorphisms observed  Consecutive change in the cyclopropyl-binding pocket Welsch, Domingues et al., Genome Biology 2008 Hartmann et al., Protein Science 2007, http://irecs.bioinf.mpi-inf.mpg.de/