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