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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”
H. Wedemeyer: 12-2012 DAAs against HCV
Drug Development against HCV
Protease- Inhibitors Polymeraseinhibitors
NI NNI
NS5A-Inhibitors
TLR-Agonists Therapeutic Vaccine
Other IFNs PEG-IFN lambda
Entry-Inhibitors
Cyclophillin Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
Promises
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
Some facts about DAAs in HCV infection
HCV is curable!
DAAs: Increase cure rates and “IFN-sparing”
H. Wedemeyer: 12-2012 DAAs against HCV
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)
Some facts about DAAs in HCV infection
H. Wedemeyer: 12-2012 DAAs against HCV
HCV is curable!
HCV is curable without interferon alpha - in vitro - in animal models - in patients
DAAs: Increase cure rates + “IFN-sparing”
Some facts about DAAs in HCV infection
H. Wedemeyer: 12-2012 DAAs against HCV
HCV is curable!
HCV is curable without interferon alpha
DAAs: increase cure rates + “IFN-sparing”
DAA combinations
Some facts about DAAs in HCV infection
- can overcome resistance development - can provide pan-genotype activity - lead to SVR close to 100%
H. Wedemeyer: 12-2012 DAAs against HCV
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
Potency Pan-genotype efficacy Resistance Barrier
+-++ + (-) + (-)
Polymerase Inhibitors nucleos(t)ides
Potency Pan-genotype efficacy Resistance Barrier
+-+++ +++
++/+++
NS5A Inhibitors
Potency Pan-genotype efficacy Resistance Barrier
+++ +/++ +/++
H. Wedemeyer: 12-2012 DAAs against HCV Wedemeyer, Nat Reviews Gastroenterol 2013
Interferon-free Combination Treatment
H. Wedemeyer: 12-2012 DAAs against HCV
… some data …
The list of compounds can never not complete, I apologize for not mentioning all promising drugs in development…
H. Wedemeyer: 12-2012 DAAs against HCV
Protease Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
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)
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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)
H. Wedemeyer: 12-2012 DAAs against HCV
Faldaprevir + PEG-IFNa/RBV Silen-C1: Phase 2 – Treatment naive
P/R 120mg LI
240mg LI
240mg No-LI
Sulkowski et al, EASL 2011
H. Wedemeyer: 12-2012 DAAs against HCV
Faldaprevir + PEG-IFNa/RBV Silen-C2: Phase 2 – Treatment experienced
Sulkowski et al, EASL 2011
H. Wedemeyer: 12-2012 DAAs against HCV
Faldaprevir + PEG-IFNa/RBV
High potency in Phase 2 studies ~ 80% qualified for shortened therapy No resistance against Q80R/K and A156S
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
NS5A Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742
NS5A Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
NS5A Inhibitors
Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742
Promising data presented at EASL and AASLD for IFN-free regimens
H. Wedemeyer: 12-2012 DAAs against HCV
NS5A Inhibitors
Daclatasvir GS-5885 ABT-267 PPI-668 MK-8742
Developed also in triple therapy with PEG-IFN/RBV
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395
20 mg daclatasvir + peg-alfa/RBV (n = 159)
60 mg daclatasvir + peg-alfa/RBV (n = 158)
20 mg daclatasvir + peg-alfa/RBV
60 mg daclatasvir + peg-alfa/RBV
Placebo + 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
Placebo + peg-alfa/RBV
Follow-up
Follow-up
Placebo + peg-alfa/RBV
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%
H. Wedemeyer: 12-2012 DAAs against HCV
Daclatasvir + PEG-IFNa/RBV Phase 2 study: Command 1; n=395
20 mg daclatasvir + peg-alfa/RBV (n = 159)
60 mg daclatasvir + peg-alfa/RBV (n = 158)
20 mg daclatasvir + peg-alfa/RBV
60 mg daclatasvir + peg-alfa/RBV
Placebo + 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
Placebo + peg-alfa/RBV
Follow-up
Follow-up
Placebo + peg-alfa/RBV
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%
H. Wedemeyer: 12-2012 DAAs against HCV
Non-Nucleoside Polymerase Inhibitors
Polymerase Inhibitors: „….buvir“.
H. Wedemeyer: 12-2012 DAAs against HCV
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
No cross-resistance between different targets Low barrier to resistance, usually not pangenotypic, 1b>1a Antiviral potency differs
H. Wedemeyer: 12-2012 DAAs against HCV
Non-Nucleoside Polymerase Inhibitors
Developed in the context of IFN-free therapies
Limited (no) role in triple therapy with PEG-IFNa/RBV
H. Wedemeyer: 12-2012 DAAs against HCV
Nucleos(t)ide Polymerase Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
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
Nucleos(t)ide Polymerase Inhibitors
H. Wedemeyer: 12-2012 DAAs against HCV
Nucleos(t)ide Polymerase Inhibitors
- Sofosbuvir (GS-7977, Gilead): Phase 3 - Mericitabine (RG-7128, Roche): Phase 2 - ALS-2200 (Alios/Vertex): Phase 2
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
Sofosbuvir
Sofosbuvir + PEG-IFNa/RBV
Sofosbuvir IFN-free
H. Wedemeyer: 12-2012 DAAs against HCV
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%
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
Promises
Next step: Cure rates >100%!!
H. Wedemeyer: 12-2012 DAAs against HCV
Problems
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
… and any problems with the new DAAs?
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
Pill-Burden? - 1-2 times per day; 1-3 pills
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
Response depending on host genetics?
IL28b may play a role (in weaker combinations)
Pill-Burden? Probably not a major issue
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
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!!!
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
Pill-Burden? Probably not a major issue Response depending on host genetics?
May be in some combinations
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?
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
Pill-Burden? Probably not a major issue Response depending on host genetics?
May be in some combinations
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?
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs?
Pill-Burden? Probably not a major issue Response depending on host genetics?
May be in some combinations
In the short-term maybe… in the long-term probably not
Side effects? Let’s wait for phase III data
Duration of therapy? 12 weeks in most cases Drug-Drug interactions? For some DAAs
Resistance?
H. Wedemeyer: 12-2012 DAAs against HCV
Any problems with the new DAAs? Pill-Burden? Probably not a major issue Response depending on host genetics?
May be in some combinations
?????
Side effects? Let’s wait for phase III data
Duration of therapy? 12 weeks in most cases Drug-Drug interactions? David will tell us
Costs? Resistance? Most likely not an issue
H. Wedemeyer: 12-2012 DAAs against HCV
To treat now or to wait?????
H. Wedemeyer: 12-2012 DAAs against HCV
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
H. Wedemeyer: 12-2012 DAAs against HCV
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
Can be treated
IFN-free
Cured IFN-free
H. Wedemeyer: 12-2012 DAAs against HCV
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
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
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