will interferon-free strategies be a reality?
DESCRIPTION
Will interferon-free strategies be a reality?. David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic www.torontoliver.ca . Disclosures. Principal Investigator in multicenter studies HCV (none for IFN-free strategies) - PowerPoint PPT PresentationTRANSCRIPT
LIVERCENTRE
Toronto Western Site
David Wong, MDUniversity of Toronto
TWH Francis Family Liver ClinicTGH Immunodeficiency Clinic
SM Positive Care Clinicwww.torontoliver.ca
Will interferon-free strategies be a
reality?
LIVERCENTRE
Toronto Western Site
Disclosures Principal Investigator in multicenter
studies HCV (none for IFN-free strategies)
BI, BMS, Johnson & Johnson, Vertex HBV
BMS, Gilead NO involvement in
Advisory Boards, Consultancy roles, Stocks
LIVERCENTRE
Toronto Western Site
Outline IFN free strategies can work Choosing optimal combinations
Exploring weaknesses of individual agents
Access to treatment Need for more drugs in each class Cost of treatment
LIVERCENTRE
Toronto Western Site
HCV genomeCombinations for cure
ProteasePol
ReplicationComplex
LIVERCENTRE
Toronto Western Site
First reportNaïve x 24 weeks
BMS-790052 (Daclatasvir) 60 mg OD NS5a replication complex inhibitor
BMS-650032 (Asunaprevir) 600 mg BID NS3 protease inhibitor
PegIFNa2a 180 ug weekly Weakness: IL28b, cirrhosis (excluded),
safety Ribavirin 1000-1200 mg OD
Weakness: resistance? AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216
LIVERCENTRE
Toronto Western Site
Results (SVR)
SVR12 SVR240
20
40
60
80
100 10090
36 36
QuadIFN-Free
11 10 11 10
*1 PCR neg 35 days later
Resistance Relapse
AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216
LIVERCENTRE
Toronto Western Site
NS5A + PIDaclatasvir (DCV) Asunaprevir (ASV)
Genotypic coverage Broad G1 and 4G1b SVR in 2/2 Works WorksG1a SVR in 2/9 Weak? WeaknessResistance Weakness WeaknessCirrhosis Not tested Not tested
Adding IFN helps IFN likely small effect (prior null
response) RBV likely even less effect (resistance)
AS Lok et al. A60. EASL 2011AS Lok et al. NEJM 2012;336:216
LIVERCENTRE
Toronto Western Site
INFORM-SVRTreatment naïve x 24 weeks
Mericitabine (MCB) 1000 mg BID Polymerase inhibitor
Danoprevir (DNV) 100 mg BID/ ritonavir 100 mg BID Macrocyclic protease inhibitor - boosted
Ribavirin 1000-1200 mg OD Treatment naïve Cirrhotics excluded
EJ Gane et al. EASL 2012
LIVERCENTRE
Toronto Western Site
Results after 24 weeks High relapse if
12 weeks treatment RBV not included
Adding IFN helps
Overall CC Non-CC0
20
40
60
80
100
26 27 25
77
50
76
1a 1b
43 21 15 4 28 17
EJ Gane et al. EASL 2012
LIVERCENTRE
Toronto Western Site
PI/r + PolI + RBVDanoprevir (DNV)/r Mericitabine (MCB)
Genotypic coverage 1, 4 and 6 Broad?G1b SVR > 70% Works but moderate Works but moderateG1a SVR ~ 25% Weakness WeaknessResistance Weakness WeaknessCirrhosis Not tested Not tested
Ribavirin needed DNV/r + MCB is weak double therapy
Adding another agent (IFN) helps G1b > 90%, G1a > 70%
Matterhorn StudyEJ Gane et al. EASL 2012
LIVERCENTRE
Toronto Western Site
Sound-C2/3PI + NNPolI +/- RBV
Faldaprevir (FDV) 120 mg OD Protease inhibitor (all except 3)
Deleobuvir (DLV) 600 mg BID Non-Nuc Polymerase Inhibitor
Sound-C21
1b >> 1a IL28b CC and Genotype 1a might respond? GI side effects: cannot keep pills down
Sound-C32 (learning from our mistakes) SVR in G1b: 19/20 (95%) SVR in G1a, IL28b CC: 2/12 (17%)
V Soriano et al. EASL 2012S Zeuzem et al. APASL 2013
LIVERCENTRE
Toronto Western Site
PI/r + PolI + RBVFaldaprevir (FDV) Deleobuvir (DLV)
Genotypic coverage 1b>1a, not 3 Broad?G1b SVR > 90% Works WorksG1a SVR ~ 17% Weakness WeaknessResistance Weakness WeaknessCirrhosis Works but moderate Works but moderate
Ribavirin needed FDV and DLV is weak double therapy Replacing RBV with another agent will
likely help
EJ Gane et al. EASL 2012
LIVERCENTRE
Toronto Western Site
ABT orals + RBV x 12 weeks
in non-cirrhotics (naïve and nulls) ABT-450/r
Protease inhibitor ABT-267
NS5a inhibitor ABT-333
Non-Nuc Polymerase Inhibitor
KV Kowdley et al. A3. EASL 2013
LIVERCENTRE
Toronto Western Site
SVR24
92 91 90 94 95 93 93 91 95 949498
94 91 8997 97 96 93
100
KV Kowdley et al. A3. EASL 2013
% S
VR
24
Mal
eFe
mal
e
1a 1b
>7
log
<7
log
F0-F
1F2
-F3
Non
-CC
CC
Mal
eFe
mal
e
1a 1b
>7
log
<7
log
F0-F
1F2
-F3
Non
-CC
CC
Naïve N=159 Null N=88
7881 10850 35124 11342 11544 56 33 55 33 22 66 41 45 85 3
LIVERCENTRE
Toronto Western Site
Salvage for BOC/TPV failures
SOF+DCV+/-RBV x 24 weeks Sofosbuvir (SOF)
Nuc Polymerase Inhibitor Declatasvir (DCV)
NS5A Replication Complex Inhibitor
MS Sulkowski et al. A1417. EASL 2013
LIVERCENTRE
Toronto Western Site
Week 2 Week 4 EOT SVR4 SVR12
91100 100 100 100
8095 100 100 95
SD SDR
SVR12%
SV
R
21 20 21 20 21 20 21 20 21 20
MS Sulkowski et al. A1417. EASL 2013
1 missed is SVR24
LIVERCENTRE
Toronto Western Site
Gilead Pipeline Ledipasvir (LDV)
NS5A Replication Complex Inhibitor GS-9669
Non-Nuc Polymerase Inhibitor Gilead plans
SOF + LDV What about SOF + LDV + GS-9669?
LIVERCENTRE
Toronto Western Site
SOF + RBV + (LDV or GS-9669)
x 12 weeks84
100 92
10
100 100
NaïveNull
% S
VR12
Electron Study: EJ Gane et al. A14. EASL 2013
N=25 N=10 N=25 N=9 N=25 N=3IL28b CC 44% 20% 36% 0 28% 13%Geno 1b 12% 10% 20% 11% 16% 90%
LIVERCENTRE
Toronto Western Site
FISSIONG2/3 Treatment naïve x 12 weeks
Sofosbuvir (SOF) 400 mg OD Polymerase inhibitor
Ribavirin (RBV) 1000-1200 mg OD Treatment naïve Cirrhotics included but Plts > 75
Compared with PegIFN-RBV (800) x 24 weeks
E Gane et al. A5. EASL 2013E Lawitz et al. NEJM 2013;368:1878
LIVERCENTRE
Toronto Western Site
SVR12
Week 2 Week 4 Week 12
Week 24
SVR12
9299 99
NA
67
32
67
9299
67
SOF-R PR
% S
VR12
251 250 244 253241 236 224 190 243
No Cirr
hosis
Cirrh
osis
No Cirr
hosis
Cirrh
osis
9891
61
34
82
6271
30
SOF-R PR
% S
VR12
59 11 145 3854 13 139 37
Genotype 2
Genotype 3Fission study: E Gane et al. A5. EASL 2013
LIVERCENTRE
Toronto Western Site
FUSIONG2/3 Difficult to treat
FUSION1 x 12 or 16 weeks IFN failures Cirrhosis 33% (Patelets > 50)
POSITRON2 x 12 weeks IFN intolerant, ineligible or unwilling Cirrhosis 15% (no platelet restriction)
1FUSION: DR Nelson et al. A6. EASL 20132POSITRON: IM Jacobson et al. A61. EASL 2013
IM Jacobson et al. NEJM 2013;368:1867
LIVERCENTRE
Toronto Western Site
SVR12SOF + RBV
No cirrhosis Cirrhosis No cirrhosis Cirrhosis
96
60
37
19
100
78
63 61
92 94
68
21
12 weeks16 weeksPositron%
SV
R12
Genotype 2
Genotype 3
26 23 10 9 38 40 26 2392 17 84 14
Genotype 3Prior treatment > 12 weeks
1FUSION: DR Nelson et al. A6. EASL 20132POSITRON: IM Jacobson et al. A61. EASL 2013
IM Jacobson et al. NEJM 2013;368:1867
LIVERCENTRE
Toronto Western Site
SummaryIFN-Free is inevitable
Challenging populations Cirrhosis Genotype 3?
Dream combo Choice of agents to
choose from Ribavirin is weak Interferon Lambda?
3 bedroom house PRT ~ 4 years+ rent SVR ~ 10 years+
rent
LIVERCENTRE
Toronto Western Site
Questions?