Actualización en nuevas terapias
para la hepatitis C
Javier García-Samaniego
Unidad de Hepatología
Hospital Carlos III. CIBERehd
Madrid
JORNADAS 2011 DE ACTUALIZACIÓN EN ATENCIÓN FARMACÉUTICA
AL PACIENTE CON PATOLOGÍAS VÍRICAS.
SOCIEDAD ESPAÑOLA DE FARMACIA HOSPITALARIA
Madrid, 13 de mayo de 2011
Evolución del tratamiento de la hepatitis C
Descubrimiento del genoma del VHC
Tratamiento con IFN alfa 3 veces/sem
durante 24 ó 48 sem. Resultados pobres
La combinación IFN + RBV mejora la respuesta
Desarrollo de Peg-IFN en monoterapia
Peg-IFN alfa más RBV terapia de referencia
Terapia basada en la respuesta viral
Desarrollo de nuevos antivirales
1989
2011
Evolución de la tasa de respuesta
RVS (%)
Todos los genotipos
100
90
80
70
60
50
40
30
19%
20
6%
10
0
1997
24 s1
1998
48 sem2
IFN
IFN + RBV
Peg-IFN-2b (12KD)
Peg-IFN-2b (12KD) + RBV
Peg-IFN -2a
Peg-IFN-2 a (48KD) + RBV
66%
41%
54%
56%
20015
20026
39%
23%
19981,2
20003
20014
20057
1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 1426
3. Zeuzem S, et al. N Engl J Med 2000; 343: 1666 4. Lindsay K, et al. Hepatology 2001; 34: 395 5. Manns M, et al. Lancet
2001; 358: 958 6. Fried M, et al. N Engl J Med 2002; 347: 975 7. Zeuzem S, et al. J Hepatol 2005; 43: 250
Respuesta virológica:
definiciones
• Respuesta fin de tratamiento (RFT)
• Niveles indetectables de ARN-VHC al final del tratamiento (24
semanas para genotipo 2/3 del VHC, 48 semanas para
genotipo 1 del VHC)
• Respuesta virológica sostenida (RVS)
• Niveles indetectables de ARN-VHC al final del seguimiento
(24 semanas después de terminado el tratamiento)
• No respuesta
• Disminución de ARN-VHC < 2 logs en el tercer mes y/o ARNVHC (+) en el 6º mes de tratamiento
• Recaída
• ARN-VHC negativo al final del tratamiento, pero de nuevo
positivo durante el período de seguimiento
Definiciones de respuesta viral rápida y temprana
Respuesta
Definición
RVR*
RNA VHC negativo (<15 IU/mL) en la semana 4
RVT**
– Completa (RVTc)
No RVR pero RNA VHC negativo (<15 IU/mL) en
la semana 12
– Parcial (RVTp)
No RVR, RNA VHC positivo en la semana 12
pero con descenso  2 log10
No-RVT
* RVR = respuesta viral rápida
** RVT = respuesta viral temprana
Descenso RNA VHC <2 log10 en la semana 12
HCV Treatment: A Lexicon of Acronyms
•
•
•
•
•
•
•
•
•
•
•
DAAs: direct antiviral agents
IL28B: IL28B polymorphism (rs12979860) genotype
test
NA: nucleoside analog polymerase inhibitors
NNI: nonnucleoside polymerase inhibitors
PI: protease inhibitors
MV: minority variants
UDPS: ultradeep pyrosequencing
vBT: viral breakthrough
RGT: response-guided therapy
eRVR: extended rapid virological response
DRM: drug-resistant mutations
SVR (%)
Genetics Predict Response: IL28B
Genotype C/C Confers Higher SVR Rates
n = 29 114 79
T/T*
T/C*
C/C*
T/T T/C C/C
10 51 47
T/T T/C C/C
4 22 8
T/T T/C C/C
Gt 1
Gt 2/3
Gt 4
*Genotype of rs12979860 on chromosome 19 (Ge D et al. Nature. 2009;461:399-401).
Strättermayer A et al. EASL 2010.
Hepatitis C: escenario en 2011
•
•
•
•
Aprobación de los primeros DAAs: telaprevir y boceprevir
Amplia utilización de estos medicamentos en la UE y EE UU
Incremento de la RVS hasta el 75% en pacientes naïves G1
Problemas potenciales con el uso de estos nuevos fármacos:
– Selección adecuada de los pacientes
– Control y monitorización inapropiados
– Manejo de los efectos adversos
– Resistencias
Tratamiento de la hepatitis C
• Tratamiento actual (PEG-IFN + Riba)
• Nuevos tratamientos
– Standard of care en 2012
• Naïves
• No respondedores
– Nuevos antivirales
•
•
•
•
Nuevos IFNs
Inhibidores de la proteasa
Inhibidores de la polimerasa
Combinaciones “libres” de IFN
Select DAAs in Clinical Development
Phase I
Phase II
Phase III
Protease Inhibitors
ABT-450
ACH-1625
GS 9451
MK-5172
VX-985
BMS-650032
CTS-1027
Danoprevir
GS 9256
IDX320
Vaniprevir
BI 201335
Boceprevir
Telaprevir
TMC435
Nonnucleoside
polymerase inhibitors
BI 207127
IDX375
ABT-333
ABT-072
ANA598
BMS-791325
Filibuvir
Tegobuvir
VX-759
VX-222
Nucleoside polymerase
inhibitors
NS5A inhibitors
IDX184
PSI-7977
RG7128-Mericitabine
A-831
PPI-461
BMS-790052
BMS-824393
CF102
Anti-HCV drugs in development
Pre Clinic
Cyclo sporine analogue
SCY-635 (Scynexis)
Cyclo sporine analogue
Debio-025 (Debiopharm)
Cyclo sporine analogue
NIM-811 ( Novartis)
Entree inhibitor
PRO-206 (Progenics)
Cyclo sporine analogue
JTK-652 (Amsterdam)
TLR agonist
ANA 773 (Anadys)
Cyclo sporine analogue
EP-CyP282 (Enanta)
Phase I
Phase II
Phase III
New treatments in AASLD 2010 & EASL 2011
• 36 Drugs
• 15 Protease Inhibitors
• 10 Polymerase Inhibitors
• 9 Other
• 240 Abstracts
Antiviral Activity of DAA Vary Among and
Within Classes
Median or Mean HCV RNA Decline (log IU/mL)
3-14 day monotherapy in genotype 1 patients
NS3 protease inhibitors
NS5A inhibitors
non-nucleoside inhibitors
nucleos/tide inhibitors
BCP, boceprevir; TVP, telaprevir. *Clinical development stopped. Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.
Efficacy & Genetic Barrier
Type of drugs
Genetic Barrier/ AV Efficacy
Other
Protease Inhibitors
Low/ High
Genotype 1
Polymerase Inhibitors Nucleoside
Analogs
High / Low-Medium
Few in develop
All genotypes
Polymerase Inhibitors Non
Nucleoside
Low/ Medium
Genotype 1
Ciclofilin Inhibitors
No/ Low
All?
NS5A Inhibitors
High/Medium-High
All?
.
Standard of care en 2012
Telaprevir
o
Boceprevir
PegIFN-α
Ribavirina
Boceprevir and Telaprevir
• Boceprevir, a potent inhibitor
of HCV NS3/4A protease
• Telaprevir, a potent inhibitor of
HCV NS3/4A protease
• Both being tested in
combination with standard-ofcare pegIFN alfa-2/RBV in
phase III studies in chronic
HCV infection
Boceprevir
– SPRINT-2: naive GT1
patients
– RESPOND-2: nonresponder
GT1 patients (partial
responders and relapsers)
Telaprevir
– ADVANCE: naive GT1
patients
– ILLUMINATE: responseguided therapy in naive GT1
paitents
– REALIZE: nonresponder
GT1 patients (null
responders, partial
responders, relapsers)
Telaprevir Phase 3 Trial: ADVANCE – GT1 Naïve
N = 350
N = 350
N = 350
8
1
2
Telaprevir
750 mg q8h
+ Peg-IFN2a
+ RBV
Telaprevir
750 mg q8h
+ Peg-IFN2a
+ RBV
no eRVR
0
3
6
2
4
Peg-IFN2a
+ RBV
4
8
6
0
Follow-up
Peg-IFN2a
+ RBV
Peg-IFN2a
+ RBV
no eRVR
Weeks
on
therapy
Follow-up
Follow-up
Peg-IFN2a
+ RBV
Peg-IFN2a
+ RBV
*eRVR = undetectable HCV RNA at week 4 and week 12
Telaprevir patients who achieve extended EVR (i.e., RVR + EVR) stop treatment after 24 weeks.
Follow-up
Follow-up
7
2
ADVANCE: SVR rates
T12PR
P<0.0001
100
Percent of patients with SVR
T8PR
90
P<0.0001
75
80
69
70
60
44
50
40
30
20
10
0
n/N =
271/363
Jacobson I, et al. AASLD 2010: Abstract 211.
250/364
SVR
158/361
PR
Telaprevir: Discontinuations
• Discontinuations due to adverse events in Phase
III ADVANCE:
Outcome, %
8-Wk TVR/PR +
16/40-Wk PR
(n = 364)
12-Wk TVR/PR
+ 12/36-Wk PR
(n = 363)
48-Wk PR
(n = 361)
Discontinuation of TVR/placebo due to
rash
7
11
1
Discontinuation of all drugs due to AEs
8
7
4
3.3
0.8
0.6
 Anemia
Jacobson IM, et al. AASLD 2010. Abstract 211.
Telaprevir Ph3 Trial: ILLUMINATE – GT1 Naïve
Non-inferiority trial requested by the FDA to specifically demonstrate that treating GT1 Naïve patients for 24 weeks was not a
disadvantage compared to treating them for 48 weeks
Weeks on therapy
2
4
1
2
Telaprevir
750 mg q8h
+ Peg-IFN2a
+ RBV
eRVR
N = 500
Peg-IFN2a
+ RBV
No eRVR
0
eRVR = undetectable HCV RNA at week 4
and week 12
*
3
6
4
8
6
0
Follow-up
Peg-IFN2a
+ RBV
Follow-up
Peg-IFN2a
+ RBV
Follow-up
7
2
ILLUMINATE:
Undetectable HCV RNA over time – ITT Population
Patients with Undetectable
HCV RNA levels (%)
100
87
80
72
72
65
60
40
20
0
n/N= 389/540
RVR
Sherman KE, et al. AASLD 2010: Abstract LB-2.
352/540
469/540
388/540
eRVR
EOT
SVR
ILLUMINATE
SVR Rates - Noninferiority of 24-week Regimen
Patients with SVR (%)
 4.5%
(2-sided 95% CI = -2.1% to +11.1%)
100
92
88
80
60
40
20
0
n/N=
149/162
T12PR24
Sherman KE, et al. AASLD, 2010: Abstract LB-2.
140/160
T12PR48
Resumen de los estudios Advance1 e Illuminate2
(Telaprevir-Fase III pacientes naïve Gt 1)
• El tratamiento “guiado” por la respuesta viral (RGT) durante
24 semanas es igual de eficaz que el de 48 semanas de
duración en pacientes con eRVR (semanas 4-12).
• La RGT es posible en 2/3 de los pacientes
• La duración más corta del tratamiento facilita el cumplimiento
y la tolerancia, y reduce los efectos secundarios.
• La duración óptima del tratamiento con TVR es de12
semanas
1. Jacobson IM, McHutchison JG,Dusheiko GM, et al. AASLD 2010: Abstract 211.
2. Sherman KE, Flamm SL, Afdhal NH, et al. AASLD 2010:LB-2.
REALIZE Study Design (N=662)*
T12/PR48
n=266
T12(DS)/
PR48
n=264
Pbo +
Peg-IFN
+ RBV
TVR + Peg-IFN +
RBV
Pbo +
Peg-IFN
+ RBV
TVR+
Peg-IFN + RBV
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Pbo/PR48
Pbo +
Peg-IFN + RBV
(control)
n=132
0
4
8
12
16
48
Weeks
72
SVR assessment
*Randomization stratified by viral load and prior response; stopping rules applied for TVR (Weeks 4, 6, and 8) and
Peg-IFN/RBV (Weeks 12, 24, and 36)
Peg-IFN = 180μg/week; RBV 1000–1200mg/day; TVR = 750mg every 8 hours ClinicalTrials.gov identifier: NCT00703118
Pbo = placebo; DS = delayed start
Zeuzem, et al. EASL 2011
24
SVR by Treatment Arms (ITT Analysis)
TVR12/PR48 (pooled TVR arms)
PR48
P < 0.01
100
Patients with SVR (%)
86%
P < 0.01
80
P < 0.01
65%
57%
60
P < 0.01
31%
40
24%
17%
15%
20
5%
0
Relapsers
(n=354)
Partial
Reponders
(n=124)
Null
Reponders
(n= 184)
Overall
(n= 662)
Zeuzem EASL 2011
Telaprevir in Genotype non-1 (C209)
Day 15 HCV-RNA Log Reduction
Gt 2
Gt 3
0
−1
−0.54
−2
−3
−4
−3.7
−5
−6
−4.85
−4.83
−5.5
T
T/P/R
P, Peg-IFNα-2a 180 μg/wk; R, ribavirin 800 mg/d; T, telaprevir q8h.
Foster G et al. EASL 2010.
P/R
−4.72
SPRINT 2: Study Design
Week 4
Control
PR
48 P/R lead-in
N = 363
Week 28
Week 48
PR + Placebo
Week 72
Follow-up
TW 8-24 HCV-RNA Undetectable
Follow-up
BOC
PR
RGT
lead-in
N = 368
PR + Boceprevir
TW 8-24 HCV-RNA Detectable
PR + Placebo
BOC/
PR
PR48 lead-in
N = 366
PR + Boceprevir
Follow-up
Follow-up
Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using
weight based dosing of 600-1400 mg/day in a divided daily dose. BOC 800 mg 3 times daily
1 Poordad F, et al. N Engl J Med 2011; 364: 1195-206.
SPRINT 2: SVR and Relapse Rates (ITT)
SVR*
Relapse Rate
p <0.0001
p =0.004
p < 0.0001
100
80
67
68
60
211
316
213
311
40
20
40
125
311
23
37
162
0
48 P/R
9
21/232
p = 0.044
80
% Patients
% Patients
100
8
18/230
53
60
40
20
0
BOC RGT BOC/PR48
Non-Black Patients
42
23
12
52
14
2/14
48 P/R
22
52
29
55
12
3/25
17
6
35
BOC RGT BOC/PR48
Black Patients
*SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week posttreatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA
documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (207/316) and 68% (210/311),
respectively and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively.
Poordad et al. NEJM 2011
Boceprevir: Adverse Events and
Discontinuations
• Anemia and dysgeusia reported more frequently in BOC
arms vs control in SPRINT-2[1-2]
Outcome
4-Wk PR + ResponseGuided BOC/PR
(n = 368)
4-Wk PR + 44-Wk
BOC/PR
(n = 366)
48-Wk PR
(n = 363)
49
49
29
• EPO use
41
46
21
 Dysgeusia[2]
37
43
18
Discontinuations due to
adverse events, %[1]
12
16
16
 Anemia[1]
2
2
1
Adverse event, %
 Anemia[1]
1. Poordad F, et al. NEJM 2011.
RESPOND-2 Study Arms and Dosing Regimen
Week 36
Week 4
Control
48 P/R
N = 80
PR
PR + Placebo
lead-in
PR
lead-in
Follow-up
Follow-up
PR + Boceprevir
TW 8 HCV-RNA Detectable/
TW 12 Undetectable
PR +
placebo
BOC/
PR48
N = 161
PR
lead-in
Week 72
TW 8 HCV-RNA Undetectable
Week 12
futility
BOC
RGT
N = 162
Week 48
PR + Boceprevir
Follow-up
Follow-up
HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12
were considered treatment failures.
(
Peginterferon P) administered subcutaneously at 1.5 μg/kg once weekly, plus Ribavirin (R)
using weight based dosing of 600-1400 mg/day in a divided daily dose
Boceprevir dose of 800 mg thrice daily
Bacon et al. N Engl J
Med 2011; 364: 1217-17.
RESPOND-2 SVR and Relapse Rates
Intention to treat population
p <0.0001
100
SVR
% of Patients
p < 0.0001
80
59
60
32
40
21
20
0
Relapse Rate
66
17
80
8
25
15
12
95 17
162 111
107 14
161 121
PR 48 BOC RGT BOC/PR48
SVR rates in BOC RGT and BOC/PR48 arm not statistically
different (OR, 1.4; 95% CI [0.9, 2.2])
12-week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where
missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58%
(94/162) and 66% (106/161), respectively.
Resumen de los estudios Sprint-21 y Respond-22
• Las pautas de tratamiento con BOC requieren un
periodo de 4 semanas de lead-in (LI) con
PEGIFN+RBV
• La RGT (viremia C indetectable en las semanas 8 y
24) es posible en la mitad de los pacientes naïve
• Se requiere un mínimo de 24 semanas de BOC
para la respuesta viral óptima en pacientes naïve
• Se requiere LI + un periodo mínimo de 32 semanas
de tratamiento con BOC/PEGIFN/RBV para los
pacientes con fallo a un tratamiento previo con
PEGIFN/RBV
1.
2.
Poordad F, et al. NEJM 2011; 364: 1195-206.
Bacon B et al. NEJM 2011; 364: 1207-17
Similarities and Differences in Phase III
Studies of TVR and BOC in GT1 Naive Pts
Parameter
TVR[1]
BOC[2]
PR lead-in?
No
Yes: 4 wks
PegIFN alfa formulation
2a
2b
PI dosing requirements
TID; administer with fatty
meal
TID
8-12 wks followed by 12-40
wks PR
24-44 wks after
4 wks PR lead-in
Qualification for shortened therapy
(response guided)
Undetectable HCV RNA until
Wk 12 of triple therapy
Undetectable HCV RNA
until Wk 24 of triple
therapy
Qualified for shortened therapy, %
58 (24 wks)
44 (28 wks)
69-75
63-66
9
9
Rash, anemia, pruritus,
nausea
Anemia, dysgeusia
Duration of PI triple therapy
SVR, %
Relapse, %
Adverse events more frequent in PI
arms
Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. N Engl J Med 2011; 364: 1195-206 .
Tratamiento de la hepatitis C
• Tratamiento actual (PEG-IFN + Riba)
• Nuevos tratamientos (DAA)
– Standard of care en 2012
• Naïves
• No respondedores
– Nuevos antivirales
•
•
•
•
Nuevos IFNs
Inhibidores de la proteasa
Inhibidores de la polimerasa
Combinaciones “libres” de IFN
Interferons in Development
 Albinterferon alfa-2b (albIFN; HGS - Novartis):
• Every-2-week injections (phase 3 completed; clinical
development stopped in EU and USA)
• Every-4-week injections (phase 2; clinical
development stopped in EU and USA))
 Locteron (Biolex, Octoplus): phase 2b
 Omega IFN (Intarcia): phase 2
 Peginterferon Lambda (IL-29; ZymoGenetics/BMS):
phase 2
• Type III IFN binding to unique receptor
Second-Generation Protease Inhibitors
-
TMC435: Tibotec
Danoprevir: ITM/Roche
BI-201335: Boehringer Ingelheim
Vaniprevir: Merck
Activity of Other Protease Inhibitors
Combined With PR in Phase II Studies
Protease Inhibitor
Trial, Phase
Patients Meeting Efficacy
Measure, % (SOC)
BI 201335-NR[1]
SILEN-C2, II
eEVR: 42-47 (NO)
SVR12: 32-47 (NO)
Danoprevir-NR[2]
II
RVR: 37*-87** (NO)
cEVR: 50*-77** (NO)
ASPIRE, IIb
RVR: 40-68-93 (NO)
eEVR: 75-90-97 (NO)
Protocol 007, IIa
RVR: 67-84 (5)*
cEVR: 74-85 (47)*
SVR: 61-84 (63)
TMC435-NR[3]
Vaniprevir (MK-7009)[4]
.
11. Sulkowski M, et al. EASL 2011. 2. Rouzier, et al. EASL 2011. *G1a. **G1b
3. Zeuzem,et al. EASL 2011. Abstract LB.. 4. Manns MP, et al. AASLD 2010. Abstract 82. *Significant
Linear
Cross-resistance of NS3 Protease Inhibitors
Telaprevir
*
*
*
Boceprevir
Macrocyclic
Narlaprevir
ITMN-191
*
*
MK-7009
TMC 435
BI 201335
*Mutations associated with in vitro resistance but not described in patients.
Susser S et al. Hepatology. 2009;50:1709-18; Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.
What Do We Currently Know About
Resistance to Protease Inhibitors?
• Minor resistant populations preexist at baseline in virtually all HCVinfected patients[1]
• Resistant variants rapidly selected with monotherapy[2]
– R155K requires 1 nucleotide change in GT1a but 2 nucleotide
changes in GT1b; virtually all resistance has been seen in GT1a[3]
• Emergence of resistance reduced when protease inhibitor combined
with potent antivirals without cross-resistance, such as pegIFN, or
pegIFN plus RBV[3,4]
• Failure to achieve SVR during triple-combination therapy associated
with selection of resistant HCV variants[3]
• Boceprevir mutations can persist at least 3 yrs after exposure.
However, telaprevir resistance mutations undetectable 2 yrs after
treatment discontinuation in 89% of patients in EXTEND study[4]
1. Bartenschlager R, et al. J Gen Virol. 2000;81:1631-1648. 2. Ozeki I. J Hepatol. 2009;50:S350.
3. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 4. Zeuzem S AASLD 2010.
Polymerase Inhibitors:
Main Characteristics
Summary
Advantages
Disadvantages
Nucleoside
Inhibitors
(Mericitabine;
IDX 184)
• Analogs of natural
substrates
• Binds active site
of NS5B,
terminates viral
RNA chain
generation
• High genetic barrier
for resistance
• Equally active in all
genotypes
• Relatively lower
antiviral efficacy
• Few in pipeline
Nonnucleoside
Inhibitors
(GS 9190; BI
207127;
filibuvir)
• Binds to various
allosteric sites,
inducing
conformational
changes in
polymerase
• Multiple target sites
identified
• Low-to-medium
antiviral efficacy
• Low genetic barrier
• HCV
genotype/subtype
dependent
• Efficacy influenced by
polymorphisms?
Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.
JUMP-C – Mericitabine + PEGASYS® + RBV
in Naïve G1/4 Patients
CHC, naïve,
G1/4, n=166
Pts with eRVR*
STOP
Mericitabine 1000 mg bid plus
PEGASYS® plus RBV
PEGASYS® plus RBV
Study
Weeks
Pts without eRVR*
PEGASYS® plus RBV
0
Randomization
* eRVR (HCV RNA <15 IU/mL from weeks 4-22)
Pockros et al, EASL 2011, late-breaker oral
24
48
JUMP-C – Virological Response –
On Treatment Interim Results
MCB / P / R
P/R
100%
HCV RNA <15 IU/mL [%]
.
91,0%
80%
63,0%
62,0%
60,0%
60%
40%
20%
0%
14,0%
13,0%
51/81 12/85
49/81 11/85
74/81 53/85
Week 4 (RVR)
Week 4-22 (eRVR)
Week 24
Pockros et al, EASL 2011, late-breaker oral
6
TF - Nulls
Naïves
5
4
3
2
1
Limit of
Detection
1
3
5
LLOD: Lower limit of detection
LLOQ: Lower limit of quantification
Gane EJ, et al. Lancet 2010.
7
Days
9
11
13
88
90
80
70
63
60
50
50
40
30
25
20
10
0
Nulls
Naïves
7
100
Nulls
Naïves
Median Log10 HCV RNA (IU/mL)
RG7128 1000 mg BID + RG7227 (Danoprevir) 900 mg BID
EOT HCV RNA < LLOQ or LLOD (%)
Other strategies: PI + Polymerase Inhibitor.
Potent Antiviral Activity in HCV G1 Interferon-Naïve and Null Responders
with a BID Regimen of RG7128 + Danoprevir: INFORM-1
<LLOD
<LLOQ
Combination Therapies with 2 or More DAAs
Presented at AASLD 2010
DRUG
COMBOS
CLASS
COMPANY
PHASE
ABSTRACT
BMS-650032+
BMS-790052
PI+NS5a
BMS
2a
LB-8
Danoprevir
(RG7227)+
RG7128
PI+NI
Roche/
2b
32, 81
GS-9190+
GS-92568
PI+NNI
Gilead
2a
LB-1
BI-201335+
BI-207127
PI+NNI
Boehringer
Ingelheim
2a
LB-7
Genetech
¿Podremos curar la hepatitis C
sin IFN?
IFN
RBV
DAA
RBV?
DAA
IFN
RBV
“A theory is something nobody believes,
except the person who made it. An
experiment is something everybody believes,
except the person who made it”
Albert Einstein