New DAAs - PIs, NS5a Inhibitors, Pol.-Inhibitors (Nucs and Non …regist2.virology-education.com/2012/2global/docs/16_wede... · 2012. 12. 15. · DAAs against HCV Disclosures Honoraria

1

New DAAs - PIs, NS5a Inhibitors,

Pol.-Inhibitors (Nucs and Non-Nucs): Promises and Problems

Heiner Wedemeyer Hannover Medical School

Germany

H. Wedemeyer: 12-2012 DAAs against HCV

Disclosures

Honoraria for consulting or speaking (last 5 years): Abbott, Abvie, Biolex, BMS, Boehringer Ingelheim, Gilead, ITS,

JJ/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV

Research grants: Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche

Diagnostics, Siemens

… and many other presenters involved in viral hepatitis will have similar disclosures. So, there is quite some interest in the field supporting

the “promises”


Drug Development against HCV

Protease- Inhibitors Polymeraseinhibitors

NI NNI

NS5A-Inhibitors

TLR-Agonists Therapeutic Vaccine

Other IFNs PEG-IFN lambda

Entry-Inhibitors

Cyclophillin Inhibitors


Promises


Some facts about DAAs in HCV infection

HCV is curable! - 10-50% spontaneous clearance in acute hepatitis C

- (almost) no late relapse (beyond FU-w24) in SVR-patients - Cure improves the clinical long-term outcome!

0 1 2 3 4 5 6 7 8 9 100

10

20

30

p



HCV is curable!

DAAs: Increase cure rates and “IFN-sparing”


HCV is curable!

DAAs: increase cure rates + “IFN-sparing”

- even in previous IFN-nonresponder patients!

e.g.: Quadruple therapy with Daclatasvir (NS5A) + Asunaprevir (PI), PEG-IFNa + Ribavirin

leads to cure in up to 100% of nonresponder patients (Lok et al., NEJM 2012)



HCV is curable!

HCV is curable without interferon alpha - in vitro - in animal models - in patients

DAAs: Increase cure rates + “IFN-sparing”



HCV is curable!

HCV is curable without interferon alpha

DAAs: increase cure rates + “IFN-sparing”

DAA combinations


- can overcome resistance development - can provide pan-genotype activity - lead to SVR close to 100%


Protease-Inhibitors „2nd wave“ vs. „2nd generation“

Potency Pan-genotype efficacy Resistance Barrier

++-+++ +/++ +/++

DAAs against HCV in clinical development

Polymerase Inhibitors Non-nucleos(t)ides


+-++ + (-) + (-)

Polymerase Inhibitors nucleos(t)ides


+-+++ +++

++/+++

NS5A Inhibitors


+++ +/++ +/++

H. Wedemeyer: 12-2012 DAAs against HCV Wedemeyer, Nat Reviews Gastroenterol 2013

Interferon-free Combination Treatment


… some data …

The list of compounds can never not complete, I apologize for not mentioning all promising drugs in development…


Protease Inhibitors


Protease inhibitors („…previrs“) Approved •Boceprevir

•Telaprevir Phase 3 •Simeprevir (TMC435)

•Faldaprevir (BI201335)

Phase 2 (phase 3 in IFN-free combin.)

•Asunaprevir •ABT-450/r •Danoprevir/r •MK-5172 •GS-9256 •GS-9451 •IDX-320 •Sovaprevir (ACH-1625)


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 (Pillar-Study – Phase 2 Treatment naive)

P/R RGT 75 mg P/R RGT 75 mg P/R RGT 150 mg P/R RGT 150 mg

Pro

porti

on o

f pat

ient

s (%

)

P< 0.05 P< 0.05 P< 0.005

• Based on RGT, 79-86% of patients were eligible to complete treatment at Week 24

Week 4 (RVR) Week 12 End of treatment SVR24

76 68

75

91 93 94 95

56

92 97

92 94

79 82 75 81 86

65 75

5

0 10 20 30 40 50 60 70 80 90

100

TMC435 12 W TMC435 24W TMC435 12W TMC435 24 W Pbo/P/R 48 W

Fried et al, AASLD 2011


SVR2

4, %

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


Simeprevir + PEG-IFNa/RBV

High potency in Phase 2 studies ~ 80% qualified for shortened therapy ~ 50% SVR in previous null-responder > 60% SVR in F3/F4 patients (Poordad, AASLD 2012)

Lower Response rates in genotype 1a (specific resistant variant: Q80R/K) Mild and transient bilirubin increase overall favorable safety profile (Fried et al., AASLD 2012)


Faldaprevir + PEG-IFNa/RBV Silen-C1: Phase 2 – Treatment naive

P/R 120mg LI

240mg LI

240mg No-LI

Sulkowski et al, EASL 2011


Faldaprevir + PEG-IFNa/RBV Silen-C2: Phase 2 – Treatment experienced

Sulkowski et al, EASL 2011


Faldaprevir + PEG-IFNa/RBV

High potency in Phase 2 studies ~ 80% qualified for shortened therapy No resistance against Q80R/K and A156S


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

of distinct resistant variants (may differ between gen 1a and 1b)

NS5A Inhibitors


Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742

NS5A Inhibitors


NS5A Inhibitors


Promising data presented at EASL and AASLD for IFN-free regimens


NS5A Inhibitors


Developed also in triple therapy with PEG-IFN/RBV


0

1

2

3

4

5

6

7

0 4 8 12 16 20 24 28 32 36 40 44 48

Mea

n HC

V RN

A (lo

g 10

IU/m

L)

Weeks

BMS-790052 3 mg QDBMS-790052 10 mg QDBMS-790052 60 mg QDPlacebo

Pol et al, Lancet Infect Diseases 2012

Daclatasvir + PEG-IFNa/RBV


Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395

20 mg daclatasvir + peg-alfa/RBV (n = 159)


20 mg daclatasvir + peg-alfa/RBV


Placebo + peg-alfa/RBV


Weeks 1-12 Weeks 13-24

Week 4 RNA Week 10 RNA

NO

YES

NO

YES

Follow- Up

Peg-alfa/RBV

Peg-alfa/RBV


Follow-up

Follow-up


Follow-up

Follow-up

Placebo + peg-alfa/RBV (n = 78)

Placebo + peg-alfa/RBV Peg-alfa/RBV

R V R

Follow-up from Weeks 24 or 48

Hezode et al., AASLD 2012

SVR

36%

65%

64%


Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395







Weeks 1-12 Weeks 13-24

Week 4 RNA Week 10 RNA

NO

YES

NO

YES

Follow- Up

Peg-alfa/RBV

Peg-alfa/RBV


Follow-up

Follow-up


Follow-up

Follow-up

Placebo + peg-alfa/RBV (n = 78)

Placebo + peg-alfa/RBV Peg-alfa/RBV

R V R

Follow-up from Weeks 24 or 48

Hezode et al., AASLD 2012

SVR

85%

83%

80%

81%


Non-Nucleoside Polymerase Inhibitors

Polymerase Inhibitors: „….buvir“.



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

No cross-resistance between different targets Low barrier to resistance, usually not pangenotypic, 1b>1a Antiviral potency differs



Developed in the context of IFN-free therapies

Limited (no) role in triple therapy with PEG-IFNa/RBV


Nucleos(t)ide Polymerase Inhibitors


Cause chain-termination (not an “inhibitor” of the polymerase)

Triphosphorylated form recquired for activity Pangenotypic activity

(highly conserved binding site) Resistant variants show very low fitness

- high genetic barrier




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


Mericitabine + Danoprevir

Gane et al., Lancet 2010

Treatment duration: 14 Days

http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6T1B-517N7TN-4&_image=B6T1B-517N7TN-4-F&_ba=&_user=1527793&_coverDate=11%2F05%2F2010&_rdoc=1&_fmt=full&_orig=search&_cdi=4886&_pii=S0140673610613840&view=c&_isHiQual=Y&_acct=C000053539&_version=1&_urlVersion=0&_userid=1527793&md5=64fd481211bca3bbca93b82ca272ff52


Mericitabine + PEG-IFNa/RBV

Wedemeyer et al., Hepatology in press

Propel-Study: Mericitabine 12 weeks Jump-C-Study: Mericitabine 24 weeks

PEG-IFNa/RBV RGT until week 48

Propel: SVR rates similar to control


Mericitabine + PEG-IFNa/RBV

Pockros et al., Hepatology in press

Propel-Study: Mericitabine 12 weeks Jump-C-Study: Mericitabine 24 weeks

PEG-IFNa/RBV RGT until week 48

Propel: SVR rates similar

Jump-C: SVR rates 20% higher


Sofosbuvir

Sofosbuvir + PEG-IFNa/RBV

Sofosbuvir IFN-free


Sofosbuvir

Sofosbuvir + PEG-IFNa/RBV

Proton: Phase 2 121 pts. Genotype 1 (Lawitz AASLD 2011)

Atomic: Phase 2 323 pts. Genotype 1 (4/6), non-cirrhotic (Kowdley EASL & AASLD 2012)

H. Wedemeyer: 12-2012 DAAs against HCV Lawitz et al. AASLD 2011

Sofosbuvir: Proton Study Phase 2

12 48 24

PSI-7977 200 mg QD PEG/RBV

PSI-7977 400 mg QD PEG/RBV

PEG/RBV

PEG/RBV

PEG/RBV N=48

N=47

N=26

HCV GT1

SVR24

SVR24

NON-eRVR PEG/RBV

NON-eRVR PEG/RBV

stop

stop

Wk 0

SVR

91%

88%


Sofosbuvir: Atomic Study Phase 2

SVR-24

89%

85%

Kowdley et al., EASL 2012 & AASLD 2012

88%

Modified Analysis excluding Lost-to-FU: SVR 94-100% No resistance selected


Promises

Next step: Cure rates >100%!!


Problems


No Triple Therapy n=103

Therapy-associated

Safety Concerns

Low Treatment Urgency:

Wait for better Options

Nonmedical Patient related

Reasons

Poor Chance

for SVR Multiple reasons influenced

the final decision

Maasoumy et al., AASLD 2012

Triple Therapy for Hepatitis C: Experiences from the Hannover Medical School Hepatitis clinic

First 208 patients evaluated for triple therapy


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=36 (40%)

N=4 Stopping rule

Maasoumy et al, AASLD 2012

Chance for SVR N=52 (60%)

Triple Therapy for Hepatitis C: Experiences from the Hannover Medical School Hepatitis clinic


… and any problems with the new DAAs?


Any problems with the new DAAs?

Pill-Burden? - 1-2 times per day; 1-3 pills



Response depending on host genetics?

IL28b may play a role (in weaker combinations)

Pill-Burden? Probably not a major issue



Pill-Burden? Probably not a major issue Response depending on host genetics?

May be in some combinations

so far not a major issue some GI symptoms, photosensitivity, bilirubin increase, ALT increases

Side effects?

… but let’s wait for the phase III study results!!!





most regimens 12 weeks, but 24 weeks may not be the solution for all 12 weeks-failures….

Side effects? Let’s wait for phase III data Duration of therapy?





Different for each single drug Studies needed not only in healthy subjects but in patients with

HCV infection and advanced liver disease!

Side effects? Let’s wait for phase III data

Duration of therapy? 12 weeks in most cases Drug-Drug interactions?





In the short-term maybe… in the long-term probably not


Duration of therapy? 12 weeks in most cases Drug-Drug interactions? For some DAAs

Resistance?


Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics?


?????


Duration of therapy? 12 weeks in most cases Drug-Drug interactions? David will tell us

Costs? Resistance? Most likely not an issue


To treat now or to wait?????


The probably most important point

All oral therapy will lead to a change in treatment paradigm

The number of treatable patients will increase dramatically!

HCV infected patients Diagnosed

patients Cured

with IFNa

Can be treated with IFNa





HCV infected patients Diagnosed

patients

Can be treated

IFN-free

Cured IFN-free





HCV infected patients Diagnosed patients Cured

IFN-free

New DAAs -�PIs, NS5a Inhibitors, �Pol.-Inhibitors (Nucs and Non-Nucs):�Promises and ProblemsDianummer 2Dianummer 3Dianummer 4Dianummer 5Dianummer 6Dianummer 7Dianummer 8Dianummer 9Dianummer 10Dianummer 11Dianummer 12Dianummer 13Dianummer 14Dianummer 15Dianummer 16Dianummer 17Dianummer 18Dianummer 19Dianummer 20Dianummer 21Dianummer 22Dianummer 23Dianummer 24Dianummer 25Dianummer 26Dianummer 27Dianummer 28Dianummer 29Dianummer 30Dianummer 31Dianummer 32Dianummer 33Dianummer 34Dianummer 35Dianummer 36Dianummer 37Dianummer 38Dianummer 39Dianummer 40Dianummer 41Dianummer 42Dianummer 43Dianummer 44Dianummer 45Dianummer 46Dianummer 47Dianummer 48Dianummer 49Dianummer 50Dianummer 51Dianummer 52Dianummer 53Dianummer 54Dianummer 55Dianummer 56Dianummer 57Dianummer 58Dianummer 59

Documents

New DAAs - PIs, NS5a Inhibitors, Pol.-Inhibitors (Nucs and Non …regist2.virology-education.com/2012/2global/docs/16_wede... · 2012. 12. 15. · DAAs against HCV Disclosures Honoraria