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

van der Meer JAMA 2013

1 2 3 4 5 6 7 8 9 10 10 20 30

p<0.001 SVR non-SVR

Time - in years LR-Mortality (%)

Standard of care for chronic hepatitis C in 2013

Pegylated interferon alpha 2 a/b Ribavirin First wave NS3/4A protease inhibitor all HCV genotypes genotype 1 only

• 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

Chronic hepatitis C – standard of care

HCV genotype 1 HCV

• ther genotypes

Pre 2011 PEG + Riba PEG + Riba Current PEG + Riba + NS3/4A protease inhibitor PEG + Riba

SVR 45% SVR 75% SVR 75% SVR 70%

Clinical trials vs real world

Patients Treated N=86 Continued after week 12 N=61 (71%) N=25 Treatment Failure „Half-Time“ Week 24/28 N=56 (65%) N=5 Discontinued

• 2 death
• 3 virological failure

Treatment failure At least n=34 (40%) N=4 Stopping rule Chance for SVR N=52 (60%)

Maasoumy AASLD 2012

The long-term goal

Drug targets in the HCV replication cycle

Modified from Fields Virology, 5th Edition.

Institut für Molekularbiologie und Klinik für Gastroenterologie, Hepatologie und Endokrinologie

Protease- Inhibitors

Polymeraseinhibitors NI NNI NS5A-Inhibitors TLR-Agonists Therapeutic Vaccine Other IFNs PEG-IFN lambda Entry-Inhibitors Cyclophillin Inhibitors

miR122- Inhibitors

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

VLDL-like lipoprotein

HCV genome

Other Other Other Other Other Other

Treatment options for chronic hepatitis C are evolving

pre 2011 2011 2012 2013 2014 2015 2016

non-specific drugs

Boceprevir (PI) Ribavirin

specific drugs

Telaprevir (PI) Pegylated inteferon Faldaprevir (PI) Simeprevir (PI) Sofosbuvir (Nuc NS5B) Daclatasvir (NS5A) ???

(Non-Nuc NS5B)

Lambda inteferon

DAA‘s currently in phase III *

NS3/4A protease inhibitors

• ABT-450/r
• Asunaprevir
• Faldaprevir
• Simeprevir
• Vaniprevir

NS5A inhibitors

• Daclatasvir
• Ledipasvir
• ABT-267

Nucleoside polymerase inhibitors Sofosbuvir Non-nucleoside polymerase inhibitors ABT-333 BI-207127

* - 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

SVR24, %

Relapsers Partial responders Null responders

Pbo TMC435 100 mg* TMC435 150 mg* Pbo TMC435 100 mg* TMC435 150 mg* Pbo TMC435 100 mg* TMC435 150 mg*

67 79 67 79 10 27 39 68 52 69 2 23 23 50 26 51 3 16

Null F4= 33% (7/21)

Simeprevir + PEG-IFNa/RBV (Aspire-Study – Phase 2 Treatment experiences)

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

• High potency at picomolar doses
• Pan-genotypic activity differs between

compounds

• Viral breakthrough is associated with selection
• f distinct resistant variants

(may differ between genotype 1a and 1b) NS5A Inhibitors

Asunaprevir (protease) + daclatasvir (NS5A) +/- Peg/Riba in previous non-responders

SVR24 = 36% SVR24 = 90%

Lok NEJM 2012

• N = 21
• Non-cirrhotic

Non-Nucleoside Polymerase Inhibitors

Polymerase Inhibitors: „….buvir“.

Fingers

Catalytic site Nucleoside analogs

Adapted from Butcher. Nature. 2001;410:235.

Thumb inhibitors

Palm

Non-Nucleoside Polymerase Inhibitors

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

Previously untreated  SVR12 = 95% Non-responders  SVR12 = 47%

• Open label
• n=50; genotype 1
• Non-cirrhotic

Poordad NEJM 2013

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

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)

SBV +P/R 12w SBV +P/R 12w  12w SBV mono or SBV/R SBV +P/R 24w

• N = 332
• Genotypes 1 > 4, 5, 6
• Previously untreated
• Non-cirrhotic

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

Adaptiert von Kieffer et al. J Antimicrob Chemother 2010

DAA-Klasse Viral target variant NS3 linear NS3 makro- cyclic NS5A- Inhibitor NS5B- Nukleosid NS5B Palm NS5B Thumb NS5B Finger IFN RBV NS3- Protease V36M T54A R155K A156T D168V R R R R S S S R R R S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S NS5A L28V Y94H S S S S R R S S S S S S S S S S S S NS5B S282T C316Y M414T R422K M423T P495S S S S S S S S S S S S S S S S S S S R S S S S S S R R S S S S S S R R S S S S S S R S S S S S S S S S S S S

Reversion to wild type after triple therapy is slow but steady

Rate of reversion to wildtype (%)

0,5 1,0 1,5 2,0 91% 71% 62% 59% 100 80 60 40 20 V36M T54S R155K Any mutation

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

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

Rapid progression to cirrhosis

• Alcohol use
• Other liver diease
• Steatosis
• Insulinresistance
• Age >50 years
• Male sex
• Smoking
• Co-infections (HBV, HIV)
• Histologically documented rapid

progression Treatment failure

• Previous poor response to

PEG/Riba

• Non-CC IL28B-genotype
• High HCV-RNA
• Advanced fibrosis
• Low LDL
• HCV-Subtype 1a
• Poor compliance / motivation
• Previous exposure to DAA‘s ?
• Preexisting resistance associated variants?

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!