Future therapies
Massimo Levrero
Department of Internal Medicine - DMISM
LEA INSERM U785
Life-Nanoscience Laboratory for Functional Genomics
Sapienza University - Rome
Potential Antiviral Targets and Approaches
IFN
Immunomodulators
Entry
IFN alfa
IFN lambda
Direct-acting
antivirals
(DAAs)
Therapeutic
vaccines
Host-targeting
antivirals
(HTAs)
Replication, polyprotein
processing and/or assembly
NS5B
polymerase
inhibitors
NS3
protease
inhibitors
NS5A
replication
complex
inhibitors
Inhibitors of
polyprotein
processing
Inhibitors of
replication
Popescu C-L & Dubuisson J. Biol Cell 2009;102:63-74.
HCV pipeline by mechanism of action
DAA combinations (17)
Phase I
Gilead
Pharmasset
Cyclophilin. I
(2)
ACH-2928
(Acillion)
Nucleoside
BI
NS5B
Japon Tonbacco
Polymerase
R0622 (Roche)
Inhibitors (8)
Medivir (Tibotec)
Preclinical
Abbott
Others (6)
Nucleotide NS5B
Polymerase
Inhibitors (4)
Phase II
BI
Vitamine D
Vertex
Nitazoxamide
ROCHE
(Romark)
BMS
Celgosivir
IFN λ
Bavituximab
(Zymogen/Novartis)
Phase III
Filed
IDX 184
(Idenix)
PSI 7977
pharmasset)
Debio025/ Taribavirin
Silibinine
NIM811
(Valeant)
SCY-835
(Novartis)
BMS 790052
(BMS)
AZD-7295 ABT267
(ABT)
(AZN)
PPI-461
MSD
GS-5885
Idenix719
NS5A inhibitors
GLS9393 (GSK)
PSI 938
R7128 (Pharmasset)
(Roche /pharmasset)
PSI-661
(Pharmasset)
Biocryst
INX 189 (Inhibitrex)
BMS791325
Filibuvir (BMS)
(PFE)
GS9190
IDX 375
(Gilead)
Boceprevir
Telaprevir
(Idenix)
Vx222
ANA598
(MSD)
(Vertex/JJ)
(Vertex)
RG7348
BI201127 (Anadys)
BI201335
(Roche)
TMC-435
(BI)
ABT333
(BI)
TMC
647055
(Tibotec/JJ)
ABT072
Vertex
ITMN191/R7227
(Tibotec)
BMS 824393
MK7009(Roche/Intermune)
(ABT)
PPI-1301 (BMS)
(MSD)
A837093
BMS650032
GSK
(BMS)
(Abbott)
ABT450
EDP-239
(ABT)
VX-916
VBY-376
GS9256 GS9451
(Enanta)
VX-759
IDX 077
ACH2684
MK5172 (Gilead) (Gilead)
(Idenix)
VX-985 (MSD)
(Achillion)
(Vertex)
IDX 079
(13)
VX-813
Non
AVL-192
(Idenix) (Vertex)
AVL-181
(Avila)
(Avila)
NS3/4A Protease inhibitors
(19)
Nuc NS5B
Polymerase inhibitors (12)
A second wave and a second generation of NS3
/ NS4A protease inhibitors
Preclinical
Phase I
Phase II
Phase III
Filed
Boceprevir
(MSD)
Telaprevir
(Vertex/JJ)
TMC-435
(Tibotec/JJ)
ITMN191/R7227
MK7009(Roche/Intermune)
(MSD)
ABT450
(ABT)
VBY-376
IDX 077
MK5172
(Idenix)
VX-985 (MSD)
(Vertex)
IDX 079
VX-813
(Idenix) (Vertex)
BI201335
(BI)
BMS650032
(BMS)
GS9256 GS9451
(Gilead) (Gilead)
AVL-181
(Avila)
AVL-192
(Avila)
NS3/4A Protease inhibitors
(19)
ACH2684
(Achillion)
Viral genotype “still” determines
the approach to HCV Therapy
• Genotypes 2 and 3
– Therapy today and in the near future will be pegIFN/RBV
• Genotype 1
– Additional option of an HCV protease inhibitor combined
with pegIFN/RBV
– Boceprevir and telaprevir approved in Europe in JulySeptember 2011
• Both indicated for untreated and previously treated HCV
• Different regimen formats
• Different criteria for shortening therapy
Phase III virological efficacy
Boceprevir ( Victrelis®) or Telaprevir ( Incivo®)
Naive patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir
Telaprevir
SVR increases from 38% to
63/66%
SVR increases from 44% to
72/75%
Poordad F et al. N Engl J Med 2011: 364: 1195-1206
Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.
Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
Phase III virological efficacy
Boceprevir ( Victrelis®) and Telaprevir (Incivo ®)
Treatment-experienced patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir
Relapsers
SVR increases from 29% to 75%
Partial-Responders
SVR increases from 7% to 52%
Telaprevir
Relapsers
SVR increases from 24% to 83/88%
Partial-responders
SVR increases from 15% to 54-59%
Null-responders
SVR increases from 5% to 29/33%
Bacon BR., et al. N Engl J Med 2011; 364:1207-1217.
Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
Both PegIFN and RBV Required in Protease
Inhibitor Combination Regimens
100
100
PROVE-2[1]
80
SPRINT-1[2]
80
60
36
40
20
0
SVR (%)
SVR (%)
60
60
50
40
36
20
TPR 12
(n = 82)
TP 12
(n = 78)
0
BPR 48 Wk BP + Low-Dose
(No Lead-in)
R (48 Wk)
(n = 16)
(n = 59)
Dosages not consistent between above studies.
1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. Kwo PY, et al. Lancet. 2010;376:705-716.
Patient groups with the greatest need for improved
therapies: TVR and BOC SVR by Patient Type
100
75-83[1,2]
SVR (%)
80
68-75[3,4]
53-62[3-4]
60
52-59[1,2]
29-38[1,6]
40
20
0
14[5]*
Relapser
Naive White/ Naive Black
Partial
Nonblack
Responder
Null
Responder
Cirrhotic
Null
Responder
*Pooled TVR arms of REALIZE trial.
1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
5. Zeuzem S, et al. EASL 2011. Abstract 5. 6. Vierling JM, et al. AASLD 2011. Abstract 931.
Probability of Resistance during Triple Therapy
Patients with virologic treatment failure during triple therapy
(break-through, stopping rules)
On-treatment virologic failure
Telaprevir
Boceprevir
60
52%
50
50
35%
40
40
30
30
19%
8%
20
60
20
(13% with
8 weeksTVR)
10
9%
10
1%
0
n.a.
0
naiv
REL
P-NR
NULL
Jacobson et al., NEJM 2011; Zeuzem et al., NEJM 2011
naiv
REL
P-NR
NULL
Bacon et al., NEJM 2011; Poordad et al., NEJM 2011
Switch TVR ↔ BOC in case of break-through?
V36A/ T54S/A V55A
M
Q80R/
K
R155K/T
/Q
A156S
A156T/V
D168A/E/G/
H/T/Y
V170A/
T
Telaprevir*
(linear)
Boceprevir*
(linear)
SCH900518*
(linear)
BILN-2061 **
(macrocyclic)
Danoprevir*
(macrocyclic)
MK-7009*
(macrocyclic)
TMC435*
(macrocyclic)
BI-201335*
(macrocyclic?)
BMS-650032*
(macrocyclic)
GS-9451*
(macrocyclic)
ABT450*
(macrocyclic)
IDX320**
(macrocyclic)
ACH1625**
(macrocyclic)
MK-5172***
(macrocyclic)
** mutations
mutations associated
in in
patients
associatedwith
withresistance
resistance
patients
**
mutations associated
in in
vitro
** mutations
associatedwith
withresistance
resistance
vitro
***
no viral
viral break-through
break-through during
monotherapy
*** no
during77days
days
monotherapy
Sarrazin
J Hepatol2011
2011ininpress
press
Sarrazin
et et
al.,al.,
J Hepatol
Challenges of Using 1st generation
Protease Inhibitors in Clinical Practice
• Increase in adverse effects
[TVR: anemia, rash] [BOC: anemia, dysgeusia]
•
•
•
•
•
Regimen complexity, TID dosing, Pill burden
Adherence
Concerns over resistance
Improved SVR rate but still room for improvement
Use restricted to genotipe 1
Efficacy
Genotype
dependency
Barrier to
resistance
(protease
inhibitors)
+++
+
+–
NS5A
+++
+–
+–
NS5B
+–
+++
+++
+–
+
+
Efficacy
Genotype
dependency
Barrier to
resistance
(protease
inhibitors)
+++
+++2
++2
NS5A
+++
+++3
++3
+++1
+++
+++
++
+
+
NS3/4A
1st wave DAAs
(nucleosides)
NS5B
(non-nucleosides)
NS3/4A
New DAAs
NS5B
(nucleosides)
NS5B
(non-nucleosides)
1e.g.
PSI-7977, PSI-938; 2e.g. MK-5172, ACH-1625; 3e.g. PPI-461
Protease Inhibitors in Clinical Development
Drug
Current Clinical
Phase
Doses per Day
Active Against
HCV Genotype
Side Effects
TMC-435
III
1
1,2,4,5,6
Bilirubinemia
BI 201335
III
1
1,2 ?
Jaundice, Rash,
Gastrointestinal
Danoprevir
II
3
1,2 ?
Gastrointestinal,
neutropenia,
ALT increase
Vaniprevir
II
2
1,2 ?
Vomiting
MK-5172
I
1
1,2,3,4,5,6
Na
Ciesek S et al, Clin Liver Dis 2011;15:597-609
New Agents Generally Maintain or Improve
Upon Efficacy in GT1 Treatment-Naive
Phase II Studies, Drug + PegIFN/RBV
Not head-to-head comparisons
100
71-83
SVR (%)
80
68-85 65-85 75-86
61-84
42-83
53-76
63-75
60
38-50
56
40
20
0
BOC or
TVR [1,2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79.
5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5.
7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088.
9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.
New Pis Improve Responses in
Difficult-to-Treat Patients
Efficacy in Null Responders
Agent
Trial, Phase
Pts Meeting Efficacy Measure, %
Telaprevir and Boceprevir[1,2]
 BOC or TVR + PR
REALIZE/PROVIDE, III
SVR: 29-38
Investigational Protease inhibitors
 BI 201335 + PR[3]
 TMC435 + PR*
 Vaniprevir + PR[4]
SILEN-C2, IIb
SVR: 21-35
ASPIRE, IIb
SVR: 41-59
IIb
SVR: 40-80
1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Vierling JM, et al. AASLD 2011. Abstract 931.
3. Sulkowski M, et al. EASL 2011. Abstract 66. 4. Lawitz E, et al. AASLD 2011. Abstract LB-13.
Quad Therapy:
Do We Have an Ideal DAA Combination?
Genotype Dependency
Antiviral Efficacy
Barrier to Resistance
+
+++
+/++
NS5A
+/++
+++
+/++
NS5B (NUC)
+++
+/++
+++
+
+/++
+
NS3A (PI)
NS5B (non-NUC)
Combine potent antiviral efficacy with high genetic barrier
Welzel T et al, Clin Liver Dis 2011;15:657-664
Combination Therapy for Null Responders

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID
(NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
US Study[1]
100
Japan Study[2]
90
90*
Daclatasvir + Asunaprevir
SVR24 (%)
80
Daclatasvir + Asunaprevir + PR
60
40
36
20
0
1. Lok A, et al. EASL 2011. Abstract 1356.
2. Chayama K, et al. AASLD 2011. Abstract LB-4.
N/A
*all genotype 1b patients.
Combination Therapy for Null Responders
Additional announced IFN-free study designs
in treatment-experienced patients
Protease inhibitor
Nucleos(t)ide analogue polymerase inhibitor
Nonnucleoside polymerase inhibitor
Drug 1
Drug 2
Overall
Regimen
TMC435 QD
PSI-7977 QD
± RBV
12 or 24 wks
ABT-450/RTV
QD
ABT-333 BID
+ RBV
Danoprevir/
RTV BID
Mericitabine
BID
+ RBV
24 wks
Combination Regimens
in GT1 Treatment-Naive Patients
Strategy: protease inhibitor (telaprevir) +
nonnucleoside polymerase inhibitor (VX222)[1]
– ± pegIFN/RBV for 12 wks, then RGT
Patients (%)
100
VX-222 400 mg BID + TVR + PR
VX-222 100 mg BID + TVR + PR
93
87
82
83
80
60
40
20
0
SVR24; 12 total wks of SVR12; 24 total wks of
therapy
therapy
1. Nelson DR, et al. AASLD 2011. Abstract LB-14.
Strategy: protease inhibitor
(ABT-450/r) + nonnucleoside polymerase
inhibitor (ABT-333 or ABT-072)*
– + RBV for 12 wks
– All 44 patients achieved cEVR
– Of 10 patients tested thus far,
9 achieved SVR24
INFORM-1: An all Oral IFN Free Regimen of
RG7128 + RG7227
100
6
TF - Nulls
Naïves
5
4
3
2
Limit of Detection
1
1
Days
3
5
7
9
11
13
80
70
63
60
50
50
40
30
20
10
0
25
<LLOD
Nulls
Naïves
7
88
90
Nulls
Naïves
EOT HCV RNA < LLOQ or LLOD (%)
Median Log10 HCV RNA (IU/mL)
RG7128 1000 mg BID + RG7227 900 mg BID
<LLOQ
LLOD: Lower limit of detection
LLOQ: Lower limit of quantification
Gane EJ, et al. Lancet 2010; 376(9751):1467-75.
SOUND-C1: BI 201335 (PI) plus BI 207127 (nonNUC) plus RBV in Naive HCV-1 Patients
Proportion of patients with HCV RNA <25 IU/mL during treatment
n/N (%)
Day 8
Day 15
Day 22
Day 29
4/15 (27)
7/15 (47)
10/15 (67)
11/15 (73)
G1a
2/10
5/10
6/10
6/10
G1b
2/5
2/5
4/5
5/5
3/17 (18)
14/17 (82)
17/17 (100)
17/17 (100)
G1a
2/8
8/8
8/8
8/8
G1b
1/8
5/8
8/8
8/8
G6e
0/1
1/1
1/1
1/1
400 mg tid BI 207127 + BI
201335 + RBV
600 mg tid BI 207127 + BI
201335 + RBV
Zeuzem S, et al. Gastroenterology in press
The SOUND-C2 study: up to 59 % of SVR-12
Ongoing Research Evaluates Potential for
All-Oral Therapy
IFN-free regimens shown to be highly
effective in GT2/3[1]
Several all-oral regimens under investigation
Protease inhibitor
NS5A inhibitor
Nucleos(t)ide analogue polymerase inhibitor
Nonnucleoside polymerase inhibitor

Drug 1
Drug 2
Drug 3
RBV
BI 201335
BI 207127
N/A
±
PSI-7977
PSI-938
N/A
±
ABT-450/ RTV
ABT-333
or ABT-072
N/A
PSI-7977
Daclatasvir
N/A
±
GS-9256
Tegobuvir
N/A
±
GS-9451
GS-5885
± Tegobuvir
±
Asunaprevir
Daclatasvir
BMS-791325
N/A
100
+
All-oral regimens of single drug + RBV also under investigation.
Nucleotide analogue PSI-7977 + RBV for 12
wks
– PegIFN included for 0, 4, 8, or 12 wks
100
100
100
100
SVR (%)
80
60
40
20
0
PSI-7977
PSI-7977
PSI-7977
PSI-7977
+ 0 wks
+ 4 wks
+ 8 wks
+ 12 wks
PegIFN
PegIFN
PegIFN
PegIFN
(IFN-free)
1. Gane EJ, et al. AASLD 2011. Abstract 34.
Planned or ongoing Phase III Trials
Telaprevir in GT1 IL28B CC patients
PSI-7977 across genotypes
PSI-7977 + R
TVR BID + PR
TVR BID + PR
PR
TMC435 in GT1 patients
TMC435 + PR
PR
TMC435 + PR
Telaprevir + VX-222 + PR in GT1
QUAD
PR
Daclatasvir in GT1/4 patients
Daclatasvir + PR
PR
Daclatasvir + PR
BI 201335 in GT1 patients
BI 201335 + PR
PR
BI 201335 + PR
BI 201335 + PR
PR
PR
Can We Make Regimens Simpler?
Can We Improve Adherence?
Several Drugs in Development Are Dosed Once or Twice Daily
QD
BID
TID
ABT-072
ABT-267
ABT 450*
ACH-1625
BI 201335
Daclatasvir
GS 5885
GS9451
IDX 184
INX-189
MK-5172
Narlaprevir*
PSI-7977
PSI-938
TMC435
ABT-333
Asunaprevir
BI 201335
BI 207127
BMS 791325
Danoprevir*
Filibuvir
GS9256
Mericitabine
Setrobuvir
Tegobuvir
Vaniprevir
VX-222
BI 207127
Danoprevir
*With RTV boosting.
Can We Make Regimens Simpler?
Can We Improve Adherence?
Fewer AEs With Some Investigational Agents
(Preliminary Data)
Agent
AEs More Frequent in
Experimental Arm vs PegIFN/RBV
Discontinuations
due to AEs, % (Wk)
Anemia, dysgeusia, neutropenia, rash, anorectal symptoms
13-14 (48)
Headache
0 (12)
ABT-333[3] (N = 18)
None
0 (12)
ABT-450/r[4] (N = 30)
None
0 (12)
Transient hyperbilirubinemia
5 (48)
Asunaprevir[7] (N = 36)
Fatigue
11 (12)
BI 201335[6] (N = 355)
GI events, jaundice, and rash
8 (48)
None
8 (12)
Danoprevir[9] (N = 194)
ALT elevation, neutropenia, nausea, diarrhea
4 (12)
Mericitabine[10] (N = 81)
None
6 (36)
PSI-7977[11] (N
None
3 (12)
Setrobuvir[12] (N = 63)
Rash
2 (12)
TMC435[13] (N = 309)
Mild bilirubin increases
7 (24)
GI events
6 (48)
Boceprevir/Telaprevir[1,2]
ABT-072[3]
(N = 27)
Alisporivir[5] (N
= 215)
Daclatasvir[8] (N
Vaniprevir[14]
= 36)
= 95)
(N = 169)
Studies displayed include those with data through at least 12 wks and with discontinuation rates lower than BOC/TVR.
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Gaultier, et al. APASL 2011.
4. Lawitz E, et al. EASL 2011. Abstract 1220. 5. Flisiak R, et al. EASL 2011. Abstract 4. 6. Bronowicki JP, et al. EASL 2011. Abstract 1195.
7. Sulkowski M, et al. EASL 2011. Abstract 60. 8. Pol S, et al. EASL 2010. Abstract 1189. 9. Terrault N, et al. AASLD 2010. Abstract 32.
10. Pockros P, et al. EASL 2011. Abstract 1359. 11. Nelson D, et al. EASL 2011. Abstract 1372. 12. Lawitz E, et al. AASLD 2010. Abstract 31.
13. Fried M, et al. AASLD 2010. Abstract LB-5. 14. Lawitz E, et al. AASLD 2011. Abstract LB-13.
Evolution of HCV Therapy
2001
2011
PegIFN/RBV
Protease inhibitor
Nucleos(t)ide polymerase inhibitor
Nonnucleoside polymerase inhibitor
NS5A inhibitor
Host targeting agent
Future
Next
?
?
Majority of protease inhibitors have
targeted genotypic coverage but
MK-5172, TMC435 have broad coverage[1,2]
Most nucleos(t)ide analogue polymerase
inhibitors are pan-genotypic
1. Brainard DM, et al. AASLD 2010. Abstract 807.
2. Fried M, et al. AASLD 2010. Abstract LB-5 .
Conclusions
• The next generation of protease inhibitors are in development
(expected to be available in 2015 or even earlier)
• Different DAA combination therapies are being evaluated in early
phase trials
– Whether Peg-IFN and/or RBV will be needed in all patientsis unclear
Final aim for a DAA combination regimen
– All oral
– QD
– Safe and well tolerable
– Pan-genotypic
– IL28-independent
– Limited resistance