Drugs for chronic hepatitis C the next 5 years Dr. Thomas von Hahn - PowerPoint PPT Presentation

Drugs for chronic hepatitis C – the next 5 years Dr. Thomas von Hahn Klinik für Gastroenterologie, Hepatologie und Endokrinologie und Institut für Molekularbiologie

Where are we now?

SVR improves overall survival in chronic hepatitis C patients with advanced fibrosis 30 SVR non-SVR LR-Mortality (%) 20 p <0.001 10 0 0 1 2 3 4 5 6 7 8 9 10 Time - in years van der Meer JAMA 2013

Standard of care for chronic hepatitis C in 2013 Pegylated interferon alpha Ribavirin First wave NS3/4A 2 a/b protease inhibitor all HCV genotypes genotype 1 only

Chronic hepatitis C – standard of care HCV HCV genotype 1 other genotypes Pre 2011 PEG + Riba PEG + Riba SVR SVR 45% 75% Current PEG + Riba + PEG + Riba NS3/4A protease SVR SVR inhibitor 70% 75% • PEG = pegylated interferon alpha2a (Pegasys; 180µg) or alpha2b (PegIntron; 1,5µg/kg) weekly • Riba = Ribavirin 800-1200 (-1400) mg daily • NS3/4A protease inhibitor = Boceprevir (3x800mg) or Telaprevir (3x750mg) daily

Clinical trials vs real world Patients Treated N=86 N=25 Treatment Failure Continued after week 12 N=5 N=61 (71%) Discontinued -2 death -3 virological failure N=4 „Half-Time“ Stopping rule Week 24/28 N=56 (65%) Chance for SVR Treatment failure N=52 (60%) At least n=34 (40%) Maasoumy AASLD 2012

The long-term goal

Drug targets in the HCV replication cycle Entry-Inhibitors TLR-Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda miR122- Inhibitors Protease- NS5A-Inhibitors Inhibitors Cyclophillin Inhibitors Polymeraseinhibitors NI NNI Modified from Fields Virology, 5th Edition. Institut für Molekularbiologie und Klinik für Gastroenterologie, Hepatologie und Endokrinologie

HCV genome HCV RNA genome HCV polyprotein C NS4B NS5B E1 E2 NS2 NS3 NS5A p7 NS4A VLDL-like lipoprotein (Lipo-)viral particle Replicase complex

Treatment options for chronic hepatitis C are evolving Other Sofosbuvir Other (Nuc NS5B) specific drugs Other Other Faldaprevir Boceprevir (PI) (PI) Daclatasvir Other (NS5A) Telaprevir Simeprevir (PI) ??? Other (PI) (Non-Nuc NS5B) pre 2011 2011 2012 2013 2014 2015 2016 non-specific Pegylated drugs inteferon Lambda inteferon Ribavirin

DAA‘s currently in phase III * NS3/4A protease inhibitors •ABT-450/r •Asunaprevir Nucleoside polymerase inhibitors •Faldaprevir Sofosbuvir •Simeprevir •Vaniprevir Non-nucleoside polymerase inhibitors ABT-333 NS5A inhibitors BI-207127 •Daclatasvir •Ledipasvir •ABT-267 * - subject to frequent change!!!

Protease Inhibitors … and this all just about the NS3/4A protease

New protease inhibitors („…previrs“)  High potency  Resistance will remain an issue for some compounds  Response-guided therapy in most phase 2 studies  Ritonavir boosting required for some PIs  Most PIs do not show sufficient efficacy against HCV genotype 3  Side effect profile and dosing better than telaprevir and boceprevir

Simeprevir + PEG-IFNa/RBV (Aspire-Study – Phase 2 Treatment experiences) Partial responders Null responders Relapsers SVR24, % 26 10 39 52 67 23 67 3 2 51 27 68 69 79 50 79 16 23 Pbo TMC435 TMC435 Pbo TMC435 TMC435 Pbo TMC435 TMC435 100 mg* 150 mg* 100 mg* 150 mg* 100 mg* 150 mg* Null F4= 33% (7/21) Zeuzem et al, EASL 2012

MK5172 + PEG-IFNa/RBV  High potency in Phase 2 studies SVR > 90%, most patients qualified for shortened therapy  No resistant variants identified in phase 2 Barnard et al., AASLD 2012  Activity against PI-resistant variants Ogert et al., AASLD 2012  ALT increases at higher doses (further developed 100-150 mg) Marcellin et al, AASLD 2012

NS5A Inhibitors

NS5A Inhibitors  High potency at picomolar doses  Pan-genotypic activity differs between compounds  Viral breakthrough is associated with selection of distinct resistant variants (may differ between genotype 1a and 1b)

Asunaprevir (protease) + daclatasvir (NS5A) +/- Peg/Riba in previous non-responders SVR24 = 36% SVR24 = 90% • N = 21 • Non-cirrhotic Lok NEJM 2012

Non-Nucleoside Polymerase Inhibitors Polymerase Inhibitors: „….buvir“.

Non-Nucleoside Polymerase Inhibitors Fingers Thumb inhibitors Catalytic site Nucleoside analogs Palm Adapted from Butcher. Nature. 2001;410:235.

Non-Nucleoside Polymerase Inhibitors Thumb domain 1 BI-207127 Thumb domain 2 Filibuvir; VX-222 Palm domain 1 Setrobuvir (ANA-598); ABT-333/ABT-072 Palm domain 2 Tegobuvir  Moderate potency  Low barrier to resistance,  usually not pangenotypic, 1b>1a  Developed in the context of IFN-free therapies  Limited (no) role in triple therapy with PEG-IFNa/RBV

All oral combination of ABT-450/r (protease) + ABT-333 (NN-polymerase) + ribavirin Non-responders  Previously untreated  SVR12 = 95% SVR12 = 47% Open label • • n=50; genotype 1 • Non-cirrhotic Poordad NEJM 2013

Nucleos(t)ide Polymerase Inhibitors

Nucleos(t)ide Polymerase Inhibitors  Cause chain-termination (not an “inhibitor” of the polymerase)  Pangenotypic activity (highly conserved binding site)  Resistant variants show very low fitness - high genetic barrier

Nucleos(t)ide Polymerase Inhibitors - Sofosbuvir (GS-7977, Gilead): Phase 3 - Mericitabine (RG-7128, Roche): Phase 2 - ALS-2200 (Alios/Vertex): Phase 2

Sofosbuvir – ATOMIC study (phase 2) • N = 332 • Genotypes 1 > 4, 5, 6 SBV SBV SBV +P/R • Previously untreated +P/R +P/R 12w  12w SBV Non-cirrhotic • 12w 24w mono or SBV/R Kowdley Lancet 2013

Daclatasvir (NS5A) + Sofosbuvir +/- RBV genotype 2/3 genotype 1 • N = 170 • Previously untreated • Non-cirrhotic Sulkowski AASLD 2012

More options & more complexity

Interferon-free combinations being investigated Wedemeyer, Nat Reviews Gastroenterol 2013

No evidence of cross-class resistance as yet DAA-Klasse NS3 Viral NS3 NS5A- NS5B- NS5B NS5B NS5B variant makro- IFN RBV target linear Inhibitor Nukleosid Palm Thumb Finger cyclic V36M R S S S S S S S S T54A R S S S S S S S S NS3- R155K R R S S S S S S S Protease A156T R R S S S S S S S D168V S R S S S S S S S L28V S S R S S S S S S NS5A Y94H S S R S S S S S S S282T S S S R S S S S S C316Y S S S S R S S S S M414T S S S S R S S S S NS5B R422K S S S S S R S S S M423T S S S S S R S S S P495S S S S S S S R S S Adaptiert von Kieffer et al. J Antimicrob Chemother 2010

Reversion to wild type after triple therapy is slow but steady 100 Rate of reversion to wildtype (%) 91% 80 71% 62% 60 59% 40 V36M T54S 20 R155K Any mutation 0 0 0,5 1,0 1,5 2,0 Years after end of treatment Vierling et al. EASL 2010

In 2013 there are a big question and a small question: Treat or wait? How to treat?

Factors to consider before initiating treatment Rapid progression to cirrhosis Treatment failure • Alcohol use • Previous poor response to PEG/Riba • Other liver diease • Non-CC IL28B-genotype • Steatosis • High HCV-RNA • Insulinresistance • Advanced fibrosis • Previous exposure to DAA‘s ? • Age >50 years • Low LDL • Male sex • Preexisting resistance associated variants? • HCV-Subtype 1a • Smoking • Poor compliance / motivation • Co-infections (HBV, HIV) • Histologically documented rapid progression Poordad et al. NEJM 2011 Zeuzem et al. NEJM 2011 Bacon et al. NEJM 2011 Berg et al., AASLD 2011 Jacobson et al. NEJM 2011 IpToDate

In 2018 there are a big question and a small question: How to treat? Treat or wait?

Conclusions • Over the next 5 years several new DAA will likely reach the market. • These will fall into up to 4 classes: − NS3/4A protease inhibitors − NS5A inhibitors − Nucleoside NS5B polymerase inhibitors − Non-nucleoside NS5B polymerase inhibitors • Most of these are being developed as combinations with interferon/ribavirin and in interferon free, all-oral combinations • All-oral regimens with good tolarability would markedly expand the number of patients that can be treated (advanced liver disease!!!) • The choice of combination regimens will grow rapidly • Individualization according to patient and virus characteristics may become very important

Thank you!