Upload
austin-horton
View
216
Download
0
Tags:
Embed Size (px)
Citation preview
Future therapies
Massimo LevreroDepartment of Internal Medicine - DMISM
LEA INSERM U785 Life-Nanoscience Laboratory for Functional Genomics
Sapienza University - Rome
Inhibitors of polyprotein processing
Inhibitors of replication
Potential Antiviral Targets and Approaches
IFN
IFN lambdaIFN alfa
Immuno-modulators
Direct-acting antivirals
(DAAs)Therapeutic
vaccinesHost-targeting
antivirals (HTAs)
Replication, polyprotein processing and/or assembly
Entry
NS5Bpolymerase inhibitors
NS3protease inhibitors
NS5Areplication
complex inhibitors
Popescu C-L & Dubuisson J. Biol Cell 2009;102:63-74.
Preclinical
Phase I
Phase II
Phase III
Filed
BoceprevirBoceprevir(MSD)(MSD)
TelaprevirTelaprevir(Vertex/JJ)(Vertex/JJ)
TMC-435TMC-435(Tibotec/JJ)(Tibotec/JJ)
MK7009MK7009(MSD)(MSD)
ITMN191/R7227 ITMN191/R7227 (Roche/Intermune)(Roche/Intermune)
BI201335BI201335(BI)(BI)
BMS650032BMS650032(BMS)(BMS)
GS9256GS9256(Gilead)(Gilead)MK5172MK5172
(MSD)(MSD)
ABT450ABT450(ABT)(ABT)
ACH2684ACH2684(Achillion)(Achillion)
BMS 790052(BMS)
AZD-7295(AZN)
BMS 824393(BMS)PPI-1301
EDP-239(Enanta)
GSK
Vertex
Idenix719MSD
Taribavirin(Valeant)
IFN λ(Zymogen/Novartis)
Debio025/ NIM811
(Novartis)
Nitazoxamide(Romark)
Silibinine
Vitamine D
BMS
BI
ROCHE
Gilead
R7128(Roche /pharmasset)
PSI 7977pharmasset)
BIJapon Tonbacco
R0622 (Roche)Medivir (Tibotec)
GLS9393 (GSK)PSI 938
(Pharmasset)
BiocrystINX 189 (Inhibitrex)
BMS791325 (BMS)Filibuvir
(PFE)GS9190 (Gilead)
ANA598 (Anadys)BI201127
(BI)
Vx222 (Vertex)
ABT333ABT072 (ABT)
IDX 375 (Idenix)
IDX 184 (Idenix)
SCY-835
PPI-461
VBY-376VBY-376
VX-985VX-985(Vertex)(Vertex)
VX-813VX-813(Vertex)(Vertex)
GS9451GS9451(Gilead)(Gilead)
RG7348(Roche)
TMC 647055 (Tibotec)
A837093(Abbott)
VX-916VX-759
CelgosivirBavituximab
AVL-181AVL-181(Avila)(Avila)
AVL-192AVL-192(Avila)(Avila)
PSI-661 (Pharmasset)
ACH-2928(Acillion)
GS-5885
Vertex
Abbott
Pharmasset
Nucleoside NS5B
Polymerase Inhibitors (8)
Nucleotide NS5B Polymerase Inhibitors (4)
Non Nuc NS5BPolymerase inhibitors (12)
NS3/4A Protease inhibitors (19)
NS5A inhibitors (13)
DAA combinations (17)
Others (6)
Cyclophilin. I (2)
IDX 077 (Idenix)
IDX 079 (Idenix)
ABT267ABT267(ABT)(ABT)
HCV pipeline by mechanism of action
Preclinical
Phase I
Phase II
Phase III
Filed
BoceprevirBoceprevir(MSD)(MSD)
TelaprevirTelaprevir(Vertex/JJ)(Vertex/JJ)
TMC-435TMC-435(Tibotec/JJ)(Tibotec/JJ)
MK7009MK7009(MSD)(MSD)
ITMN191/R7227 ITMN191/R7227 (Roche/Intermune)(Roche/Intermune)
BI201335BI201335(BI)(BI)
BMS650032BMS650032(BMS)(BMS)
GS9256GS9256(Gilead)(Gilead)MK5172MK5172
(MSD)(MSD)
ABT450ABT450(ABT)(ABT)
ACH2684ACH2684(Achillion)(Achillion)
VBY-376VBY-376
VX-985VX-985(Vertex)(Vertex)
VX-813VX-813(Vertex)(Vertex)
GS9451GS9451(Gilead)(Gilead)
AVL-181AVL-181(Avila)(Avila)
AVL-192AVL-192(Avila)(Avila)
NS3/4A Protease inhibitors (19)
IDX 077 (Idenix)
IDX 079 (Idenix)
A second wave and a second generation of NS3 / NS4A protease inhibitors
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 July-
September 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®)
BoceprevirSVR increases from 38% to
63/66%
Naive patients Increased SVR compared to Peg-IFN/RBV
TelaprevirSVR increases from 44% to
72/75%
Poordad F et al. N Engl J Med 2011: 364: 1195-1206Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
BoceprevirRelapsers
SVR increases from 29% to 75%
Partial-Responders SVR increases from 7% to 52%
Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV
TelaprevirRelapsers
SVR increases from 24% to 83/88%
Partial-responders SVR increases from 15% to 54-59%
Null-respondersSVR increases from 5% to 29/33%
Phase III virological efficacy Boceprevir ( Victrelis®) and Telaprevir (Incivo ®)
Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
PROVE-2[1]
SV
R (
%)
0
20
40
60
80
100
BPR 48 Wk(No Lead-in)
(n = 16)
BP + Low-Dose
R (48 Wk)(n = 59)
SPRINT-1[2]
36
50
36
60
Both PegIFN and RBV Required in Protease Inhibitor Combination Regimens
1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. Kwo PY, et al. Lancet. 2010;376:705-716.
Dosages not consistent between above studies.
TPR 12 (n = 82)
TP 12 (n = 78)
SV
R (
%)
0
20
40
60
80
100
Patient groups with the greatest need for improved therapies: TVR and BOC SVR by Patient Type
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.
0
20
40
60
80
100
SVR
(%)
Relapser Naive White/Nonblack
Null Responder
Naive Black Partial Responder
Cirrhotic Null
Responder
68-75[3,4]
53-62[3-4]
*Pooled TVR arms of REALIZE trial.
75-83[1,2]
52-59[1,2]
29-38[1,6]
14[5]*
Probability of Resistance during Triple Therapy
Patients with virologic treatment failure during triple therapy (break-through, stopping rules)
Jacobson et al., NEJM 2011; Zeuzem et al., NEJM 2011
0
10
20
30
40
50
60
naiv REL P-NR NULL
On-
trea
tmen
t viro
logi
c fa
ilure
8%(13% with
8 weeksTVR)
Telaprevir
1%
19%
52%
Bacon et al., NEJM 2011; Poordad et al., NEJM 2011
0
10
20
30
40
50
60
naiv REL P-NR NULL
9%
n.a.
Boceprevir
35%
Switch TVR ↔ BOC in case of break-through?
Sarrazin et al., J Hepatol 2011 in press
V36A/M
T54S/A
V55A 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 associated with resistance in patients ** mutations associated with resistance in vitro*** no viral break-through during 7 days monotherapy
Sarrazin et al., J Hepatol 2011 in press* mutations associated with resistance in patients ** mutations associated with resistance in vitro*** no viral break-through during 7 days monotherapy
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
1st wave DAAs
EfficacyGenotype
dependencyBarrier to resistance
NS3/4A(protease inhibitors)
+++ + + –
NS5A +++ + – + –
NS5B (nucleosides)
+ – +++ +++
NS5B (non-nucleosides)
+ – + +
EfficacyGenotype
dependencyBarrier to resistance
NS3/4A (protease inhibitors)
+++ +++2 ++2
NS5A +++ +++3 ++3
NS5B (nucleosides) +++1 +++ +++
NS5B (non-nucleosides)
++ + +
New DAAs
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
0
20
40
60
80
100
SVR
(%)
71-83 68-85 65-85 75-86 61-84BI 2
01335[
3]
Danopre
vir[4
]Nar
lapre
vir[5
]
TMC435[
6]
Vanipre
vir[7
]
BOC or TVR [1,2]
63-75
38-50
Filibuvir
[8]
56
Tego
buvir[9
]
42-83
Daclat
asvir
[10]
53-76
Alisporiv
ir[1
1]
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.
Not head-to-head comparisons
New Pis Improve Responses in Difficult-to-Treat Patients
Efficacy in Null RespondersAgent 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] SILEN-C2, IIb SVR: 21-35 TMC435 + PR* ASPIRE, IIb SVR: 41-59 Vaniprevir + PR[4] 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
NS3A (PI) + +++ +/++
NS5A +/++ +++ +/++
NS5B (NUC) +++ +/++ +++
NS5B (non-NUC) + +/++ +
Combine potent antiviral efficacy with high genetic barrier
Welzel T et al, Clin Liver Dis 2011;15:657-664
Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
Combination Therapy for Null Responders
1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.
100
80
60
40
20
0
36
Daclatasvir + Asunaprevir
Daclatasvir + Asunaprevir + PR
SVR2
4 (%
)
90 90*
N/A
US Study[1] Japan Study[2]
*all genotype 1b patients.
Additional announced IFN-free study designs in treatment-experienced patients
Combination Therapy for Null Responders
Drug 1 Drug 2 Overall Regimen
TMC435 QD PSI-7977 QD ± RBV12 or 24 wks
ABT-450/RTV QD
ABT-333 BID + RBV
Danoprevir/ RTV BID
Mericitabine BID
+ RBV24 wks
Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor
Combination Regimens in GT1 Treatment-Naive Patients
Strategy: protease inhibitor (telaprevir) + nonnucleoside polymerase inhibitor (VX-222)[1]
– ± pegIFN/RBV for 12 wks, then RGT
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 SVR24100
80
60
40
20
0
Patie
nts
(%)
9382 87 83
VX-222 400 mg BID + TVR + PRVX-222 100 mg BID + TVR + PR
SVR24; 12 total wks of therapy
SVR12; 24 total wks of therapy
1. Nelson DR, et al. AASLD 2011. Abstract LB-14.
INFORM-1: An all Oral IFN Free Regimen of RG7128 + RG7227
RG7128 1000 mg BID + RG7227 900 mg BID
Days1 3 5 7 9 11 13
Limit of DetectionMed
ian
Log 10
HCV
RN
A (IU
/mL)
1
2
3
4
5
6
7
TF - Nulls
Naïves
LLOD: Lower limit of detection LLOQ: Lower limit of quantification
Gane EJ, et al. Lancet 2010; 376(9751):1467-75.
50
25
0
10
20
30
40
50
60
70
80
90
100
<LLOQ<LLOD
88
63
Nul
ls Nul
ls
Naï
ves
Naï
ves
EOT
HCV
RN
A <
LLO
Q o
r LLO
D (%
)
SOUND-C1: BI 201335 (PI) plus BI 207127 (non-NUC) 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
400 mg tid BI 207127 + BI 201335 + RBV 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
600 mg tid BI 207127 + BI 201335 + RBV 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
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
Several all-oral regimens under investigation
Drug 1 Drug 2 Drug 3 RBV
BI 201335 BI 207127 N/A ±
PSI-7977 PSI-938 N/A ±
ABT-450/ RTV ABT-333or 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
Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor
NS5A inhibitor
All-oral regimens of single drug + RBV also under investigation.
IFN-free regimens shown to be highly effective in GT2/3[1]
Nucleotide analogue PSI-7977 + RBV for 12 wks– PegIFN included for 0, 4, 8, or 12 wks
100
80
60
40
20
0
SVR
(%)
100 100 100 100
PSI-7977 + 0 wks PegIFN
(IFN-free)
PSI-7977 + 4 wksPegIFN
PSI-7977 + 8 wksPegIFN
PSI-7977 + 12 wksPegIFN
1. Gane EJ, et al. AASLD 2011. Abstract 34.
Planned or ongoing Phase III Trials
TVR BID + PR
TVR BID + PR PR
Telaprevir in GT1 IL28B CC patients
PSI-7977 + RPSI-7977 across genotypes
TMC435 + PR
TMC435 + PR PR
PRTMC435 in GT1 patients
BI 201335 + PR
BI 201335 + PRPR
PR
BI 201335 in GT1 patients
BI 201335 + PRPR
Daclatasvir + PRPR
Daclatasvir in GT1/4 patients
Daclatasvir + PR
QUADTelaprevir + VX-222 + PR in GT1
Can We Make Regimens Simpler?Can We Improve Adherence?
Several Drugs in Development Are Dosed Once or Twice Daily
*With RTV boosting.
QD
ABT-072ABT-267ABT 450*ACH-1625BI 201335Daclatasvir
GS 5885GS9451IDX 184INX-189
MK-5172Narlaprevir*
PSI-7977PSI-938TMC435
BID
ABT-333AsunaprevirBI 201335BI 207127
BMS 791325Danoprevir*
FilibuvirGS9256
MericitabineSetrobuvirTegobuvirVaniprevir
VX-222
TID
BI 207127Danoprevir
Fewer AEs With Some Investigational Agents (Preliminary Data)
Agent AEs More Frequent in Experimental Arm vs PegIFN/RBV
Discontinuations due to AEs, % (Wk)
Boceprevir/Telaprevir[1,2] Anemia, dysgeusia, neutropenia, rash, anorectal symptoms 13-14 (48)
ABT-072[3] (N = 27) Headache 0 (12)
ABT-333[3] (N = 18) None 0 (12)
ABT-450/r[4] (N = 30) None 0 (12)
Alisporivir[5] (N = 215) Transient hyperbilirubinemia 5 (48)
Asunaprevir[7] (N = 36) Fatigue 11 (12)
BI 201335[6] (N = 355) GI events, jaundice, and rash 8 (48)
Daclatasvir[8] (N = 36) 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 = 95) None 3 (12)
Setrobuvir[12] (N = 63) Rash 2 (12)
TMC435[13] (N = 309) Mild bilirubin increases 7 (24)
Vaniprevir[14] (N = 169) GI events 6 (48)
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.
Can We Make Regimens Simpler?Can We Improve Adherence?
Evolution of HCV Therapy
2001 2011 Future
PegIFN/RBVProtease inhibitorNucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitorNS5A inhibitorHost targeting agent
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