Triple Therapy TodayPhase III Results in G1
Relapsers and Non Responders – Telaprevir
5th Paris Hepatitis Conference
Paris, 30. January 2012
Stefan ZeuzemGoethe University HospitalFrankfurt a.M., Germany
How should we define failure to prior Peg-IFN/RBV therapy?
Detection limit
RelapseNull response
BreakthroughPartial response
Treatment
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
HC
V R
NA
leve
l
Weeks
2 log10 drop
Non-response
Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22
Peg-IFN: P: peginterferon; RBV: R: ribavirinHCV: hepatitis C virus
LOQ = limit of quantification (25 IU/mL); LOD = limit of detection (10 IU/mL)
Viral curves in prior study with Peg-IFN/RBV
Week
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
Viral curves in Study 107 with telaprevir-based regimen
WeekTelaprevir + PR PR
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
PR
Study 107: viral curves through to Week 24 for prior relapsers
Shiffman ML, et al. 59th AASLD 2008, San Francisco, CA, October 31–November 4 2008
SVR 90%SVR 90%(26/29)(26/29)
Shiffman M, et al. 59th AASLD 2008, San Francisco, CA, October 31–November 4 2008
Viral curves in prior study with Peg-IFN/RBV
Week
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
Viral curves in Study 107 with Telaprevir-based regimen
WeekTelaprevir + PR PR
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
Partial responder: ≥2-log10 drop at Week 12, but had detectable HCV RNA at Week 24LOQ = 25 IU/mL; LOD = 10 IU/mL
PR
Study 107: viral curves through Week 24 for partial responders
SVR 55%SVR 55%(16/29)(16/29)
Viral curves in prior study with Peg-IFN/RBV
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
WeekTelaprevir + PR PR
Log 1
0(H
CV
RN
A)
8
7
6
5
4
3
2
1
00 1234 6 8 10 12 14 16 20 24
LOQLOD
Null responder: <1-log10 drop in HCV RNA at Week 24 or, <2-log10 drop in HCV RNA by Week 12LOQ = 25 IU/mL; LOD = 10 IU/mL
Study 107: viral curves through Week 24 for null responders
Shiffman M, et al. 59th AASLD 2008, San Francisco, CA, October 31–November 4 2008
Week
Viral curves in Study 107 with Telaprevir-based regimen
PR
SVR 57%SVR 57%(16/28)(16/28)
REALIZE: Study Design (N=662)
484 160 128Weeks
72
T12/PR48Peg-IFN + RBVTVR +
Peg-IFN + RBV Pbo +
Peg-IFN + RBV N=266 Follow-up
SVR assessment
TVR + Peg-IFN + RBV Peg-IFN + RBV
LI T12/PR48N=264
Follow-upPbo +
Peg-IFN + RBV
Pbo/PR48 (control) Pbo +
Peg-IFN + RBV Peg-IFN + RBVN=132
Follow-up
Randomization was stratified by viral load and prior response. Stopping rules applied for TVR (Weeks 4, 6, and 8 for T12/PR48; Weeks 8, 10 and 12 for LI T12/PR48) and Peg-IFN/RBV (Weeks 12, 24, and 36 for T12/PR48; Weeks 16, 24 and 36 for LI
T12/PR48)Peg-IFN: Peg-IFN alfa-2a = 180μg/week; RBV = 1000–1200mg/day; TVR = 750mg every 8 hours
ClinicalTrials.gov identifier: NCT00703118LI = lead-in; Pbo = placebo; TVR = telaprevir
REALIZE: Baseline Characteristics
*Determined using the HCV COBAS TaqMan® assay version 2.0; ‡Determined by NS3 sequencing; §Defined by local pathologists
REALIZE: Undetectable Viral Load over Time in Prior Relapsers
T12/PR48 prior relapsers (n=145)LI T12/PR48 prior relapsers (n=141)Pbo/PR48 prior relapsers (n=68)
100
90
80
70
60
50
40
30
20
10
00
Patie
nts
with
und
etec
tabl
e H
CV
RN
A (%
±SE
)
Time (weeks)8 164 12 24 48 60 72
Treatment phase Follow-up phase
Undetectable HCV RNA defined as <25 IU/mL
REALIZE: Undetectable Viral Load over Time in Prior Partial and Prior Null Responders
100
90
80
70
60
50
40
30
20
10
00 8 164 12 24 48 60 72
Treatment phase Follow-up phase
Time (weeks)T12/PR48 prior partial responders (n=49)LI T12/PR48 prior partial responders (n=48)Pbo/PR48 prior partial responders (n=27)
T12/PR48 prior null responders (n=72)LI T12/PR48 prior null responders (n=75)Pbo/PR48 prior null responders (n=37)
Patie
nts
with
und
etec
tabl
e H
CV
RN
A (%
±SE
)
Undetectable HCV RNA defined as <25 IU/mL
REALIZE: Phase 3 Trial in Tx-Experienced HCV-1 Infected Patients
8388
24
59 54
15
29 33
50
20
40
60
80
100
Relapser Partial Responder Null Responder
P/R/T(simultaneous)P/R/T(lead-in)P/R
Zeuzem et al., NEJM 2011
Sus
tain
ed v
irolo
gic
resp
onse
rate
s (%
)
Peginterferon alfa-2a 180 µg qwPeginterferon alfa-2a 180 µg qwRibavirin 1000-1200 mg/dayRibavirin 1000-1200 mg/dayTelaprevirTelaprevir 750 mg q8h 750 mg q8h
(n=354)(n=354) (n=124)(n=124) (n=184)(n=184)
Role of PEG/RBV lead-in phase• Virologic value of LI phase is questionable
– SPRINT-1: higher SVR rates with lead-in (but small number of patients)
– REALIZE: Lead-in phase did not affect breakthrough, relapse and SVR rates
• Lead-in may be clinically useful if physician is willing to take decisions at week 4– only PEG/RBV, no PI in excellent initial virologic responders
(RVR)– stop therapy in patients with poor initial virologic response (< 1
log) to avoid treatment failure and selection of resistant variants
• Improve adherence
REALIZE: SVR by Baseline Fibrosis Stage and Prior Response
Prior relapsers
Prior partial responders
Prior null responders
2/15n/N= 53/62144/167 12/38 0/510/1834/47 3/17 0/915/3811/32 1/5
No, minimal or portal fibrosis
CirrhosisStage
Pooled T12/PR48
Pbo/PR48
SVR
(%)
2/1548/57 24/59 1/18 7/50 1/10
Bridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
REALIZE: SVR by HCV Subtype and Prior Response
Prior relapsers
Prior partial responders
Prior null responders
6/31n/N= 123/140119/142 10/34 1/1027/4026/55 3/16 1/2022/5924/88 1/17
1a 1b 1b 1bHCV subtype 1a 1a
Pooled T12/PR48
Pbo/PR48
SVR
(%)
SVR Rates in LI T12/PR48 Arm by HCV RNA Reduction at Week 4 and Prior Response
Patie
nts
(%)
100
80
60
40
20
0
94
5954
SVR rate
6256
15
SVR rate Proportion of patients
90
60
41
≥1 log10 HCV RNA reduction at Week 4
10
40
59
Prior relapsers Prior partial responders Prior null responders
Proportion of patients
<1 log10 HCV RNA reduction at Week 4
90
58
30
Overall SVR rate
Overall
Overall Baseline IL28B Genotype Distribution
CC
Patie
nts
(%)
n/N=
Pooled T12/PR48
76/422
Pbo/ PR48
17/105
CT TT
Pooled T12/PR48
266/422
Pbo/ PR48
58/105
Pooled T12/PR48
80/422
Pbo/ PR48
30/105
SVR Rates by IL28B Genotype and Prior Response
Prior relapsers
Patie
nts
achi
evin
g SV
R (%
)
Prior partial responders
Prior null responders
CC CT TT CC CT TT CC CT TT
Pooled T12/PR48 (n=209)Pbo/PR48 (n=52)
Pooled T12/PR48 (n=79)Pbo/PR48 (n=20)
Pooled T12/PR48 (n=134)Pbo/PR48 (n=33)
51/58 4/12 100/117 6/30 29/34 3/10 5/8 1/5 33/57 2/10 10/14 0/5 4/10 27/92 1/18 10/32 1/15n/N=
n/a
REALIZE: AEs Occurring in ≥25% of Patients During any Treatment Phase
Patients, n (%)T12/PR48 (N=266)
LI T12/PR48 (N=264)
Pbo/PR48(N=132)
Fatigue 145 (55) 131 (50) 53 (40)
Pruritus 138 (52) 132 (50) 36 (27)
Headache 112 (42) 109 (41) 49 (37)
Rash 99 (37) 95 (36) 25 (19)
Nausea 94 (35) 87 (33) 31 (23)
Influenza-like illness 85 (32) 94 (36) 33 (25)
Anemia 79 (30) 94 (36) 20 (15)
Anorectal symptoms 75 (28) 59 (22) 10 (8)
Insomnia 68 (26) 84 (32) 34 (26)
Diarrhea 66 (25) 69 (26) 18 (14)
Pyrexia 60 (23) 71 (27) 36 (27)
Cough 62 (23) 66 (25) 26 (20)
Asthenia 51 (19) 60 (23) 38 (29)
AE = adverse event
T12/PR48 (N=266)
LI T12/PR48 (N=264)
Pbo/PR48(N=132)
Discontinuation of all study drugs during TVR treatment phase, n (%)
Any AERash events
Anemia events
Pruritus
Anorectal signs and symptoms
17 (6)2 (1)
2 (1)
0
2 (1)
11 (4)2 (1)
2 (1)
1 (<1)
0
4 (3)0
0
0
0
Discontinuation of TVR or Pbo during TVR treatment phase, n (%)
Any AERash events
Anemia events
Pruritus
Anorectal signs and symptoms
39 (15)12 (5)
6 (2)
1 (<1)
2 (1)
29 (11)10 (4)
9 (3)
3 (1)
1 (<1)
4 (3)0
0
0
0
REALIZE: AEs Leading to Study Drug Discontinuation
Telaprevir and Boceprevir - Resistance
Sarrazin & Zeuzem; Sarrazin & Zeuzem; GastroenterologyGastroenterology 2010; 138:447-62 2010; 138:447-62
V36M + R155K V36M + R155K HCV-1a:HCV-1a: 2 steps 2 steps required required
(clinically observed)(clinically observed)HCV-1b:HCV-1b:4 steps 4 steps required required
(not yet clinically observed)(not yet clinically observed)
TVR BOCV36A/M + +T54S/A + +V55A in vitro +R155K/T/Q + +A156S + +A156T/V + in vitro
D168A/V/TV170A/T in vitro +
AGGAGG AAAAGG(R155) (R155K)(R155) (R155K)
CGGCGG AAGG GG AAAAGG(R155) (R155) (R155K)(R155) (R155) (R155K)
HCV-1aHCV-1a
HCV-1bHCV-1b
0.6
Prob
abili
ty
Time after failure (months)
Probability of Resistant Variant by Subtype
Time (months)
1a 1b
0 16% 46%
3 22% 66%6 32% 87%12 60% 98%16 94% 100%
• Significant difference (p<0.0001) between subtypes for the time to become WT by population sequencing (median, 95% CI)
• HCV-1a: 10 months (9,11)• HCV-1b: 0.8 months (0,2)
0.00.10.20.30.40.5
0.70.80.91.0
0 2 4 6 8 10 12 14 16 18 1 Based on Kaplan-Meier estimation using population sequencing; hash marks in plot indicate censored observations
Probability of a patient being WT 1
median
Sherman et al., AASLD 2011Sherman et al., AASLD 2011
• 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is >20 g, eg, 1/2-cup nuts or 2-oz cheddar cheese)
• Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Wk 48)
No eRVR; PRNo eRVR; PR
Telaprevir in Genotype 1 Patients
TVR + PRTVR + PReRVR; stop at Wk 24eRVR; stop at Wk 24
PRPR
Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.
Time Point Criterion Stopping RuleWk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapyWk 24 Detectable HCV RNA Discontinue PRAny Discontinuation of PR for any reason Discontinue TVR
Treatment Naive and Previous RelapsersTreatment Naive and Previous Relapsers
Previous Partial or Null RespondersPrevious Partial or Null Responders
TVR + PRTVR + PR
484800 2424121244
PRPR
wkswks
Conclusions• Substantial increases in SVR in tx-experienced patients with Telaprevir +
P/R • Strict stopping/futility rules• Additive side effects of PIs to PEG-IFN/RBV• Both, previous response and on-treatment PEG-IFN/RBV response (lead-in)
are strong predictors of SVR• IL28B less important with potent DAAs• Lead-in phase does not affect virologic response rates, but may be applied
as a decision tool• Further improvements in particular required for previous null responders• Insufficient data for patients with high unmet need (e.g. cirrhosis, post-Ltx,
HIV/HCV coinfected patients)• DAA combinations and Quad therapies in development