clinicaloptions.com/hepatitis highlights from berlin 2011 march 30 - april 3, 2011 berlin, germany...

clinicaloptions.com/hepatitisHighlights From Berlin 2011

March 30 - April 3, 2011Berlin, Germany

Highlights From Berlin 2011CCO Independent Conference Coverage of the 46th Annual Meeting of the European Association for the Study of the Liver*

This program is supported by an educational grant from

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

This program is supported by educational grants from


About These Slides

Our thanks to the presenters who gave permission to include their original data

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.


Faculty

Nezam H. Afdhal, MD, FRCPIAssociate Professor of MedicineHarvard Medical SchoolChief of HepatologyBeth Israel Deaconess Medical CenterBoston, Massachusetts

Paul Martin, MDProfessor of MedicineChief, Division of HepatologyCenter for Liver DiseaseUniversity of Miami School of MedicineMiami, Florida


Disclosures

Nezam H. Afdhal, MD, FRCPI, has disclosed that he has received consulting fees and contracted research with GlaxoSmithKline, Merck, Pharmasset, Spring Bank, and Vertex.

Paul Martin, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Genentech, Merck, Salix, and Vertex; fees for non-CME services from Bristol-Myers Squibb and Vertex; and contracted research with Bristol-Myers Squibb, Gilead Sciences, Genentech, and Vertex.

Phase III Studies of Protease Inhibitors


REALIZE: Telaprevir + PegIFN/RBV in GT1 HCV Pts Who Failed Previous PegIFN/RBV International, multicenter, randomized, double-blind, placebo-

controlled phase III trial

Zeuzem S, et al. EASL 2011. Abstract 5.

Patients with GT 1 HCV who previously failed pegIFN/RBV

(N = 632)

Telaprevir 750 mg q8h + PR*

(n = 266)

Placebo +PR*

(n = 264)

Placebo + PR*(n = 132)

Week 4

Telaprevir 750 mg q8h+ PR*

PR*

PR*

Week 12 Week 16 Week 482:2:1 randomization; stratified by HCV RNA and

previous response

*PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.

PR*

Placebo +PR*

24-wkfollow-up for SVR


REALIZE: SVR According to Previous Response

Zeuzem S, et al. EASL 2011. Abstract 5. Graphic used with permission.

100

80

60

40

20

0

SV

R (

%)

PreviousRelapsers

Previous Partial Responders

Previous NullResponders

*P < .001 vs PR48.LI, lead-in.

83* 88*

24

59*54*

15

33*29*

5

T12/PR48

LI-T12/PR48

PR48 T12/PR48

LI-T12/PR48

PR48 T12/PR48

LI-T12/PR48

PR48

n/N= 121/145 16/68 29/49 26/48 4/27 21/72 25/75 2/37124/141


REALIZE: SVR by Baseline Fibrosis Stage and Previous Response


SVR, % Pooled T12/PR48 PR48

Previous relapsers

No, minimal, or portal fibrosis 86 32

Bridging fibrosis 85 13

Cirrhosis 84 13

Previous partial responders



Cirrhosis 34 20

Previous null responders



Cirrhosis 14 10


Subanalysis of ADVANCE: Role of IL28B in Response to Treatment With Telaprevir ADVANCE: phase III study of genotype 1, treatment-naive chronic hepatitis C

– T12PR: TVR + PR for 12 wks, then RGT with PR through Week 24 or 48

– T8PR: TVR + PR for 8 wks, placebo + PR for 4 wks, then RGT with PR through Week 24 or 48

– PR: placebo + PR or 12 wks, then PR through Week 48

42% (454 of 1088) of patients available for IL28B analysis; all patients in analysis were white

TVR increased SVR rates across IL28B genotypes, but CC still did better

CC patients tended to have better opportunity for RVR and shortened therapy

Jacobson I, et al. EASL 2011. Abstract 1369. Graphics used with permission.

SVR Rates in Patients Genotyped for IL28B

SV

R (

%)

T12PR T8PR PR

60

100

80

40

20

0n/N = 45/50 38/45 35/55

CC48/68 43/76 20/80

CT16/22 19/32 6/26

TT

90 84

6471

57

25

7359

23

SVR Rates in Patients With RVR

n/N = 39/42 30/32 9/9CC

36/41 34/47 2/2CT

10/13 14/16 0/0TT

93 94100

8872

100

7788


Subanalysis of Phase III Boceprevir Trials: SVR in Advanced Fibrosis/CirrhosisSPRINT-2: GT1 treatment-naive

PR 4 wks, then BOC + PR 44 wks

PR 4 wks, then BOC + PR for 24 wks, then stop or PR + placebo 20 wks (RGT)

PR 4 wks, then PR + placebo 44 wks

RESPOND-2: GT1 relapsers and partial responders to pegIFN/RBV

PR 4 wks, then BOC + PR 44 wks

PR 4 wks, then BOC + PR for 32 wks, then stop or PR + placebo 12 wks (RGT)

PR 4 wks, then PR + placebo 44 wks

Bruno S, et al. EASL 2011. Abstract 7. Graphics used with permission. F3/4 F0/1/2

100

80

60

40

20

0

SV

R (

%)

F0/1/2

38

6767

384152

328319n= 313 243442

100

80

60

40

20

0

SV

R (

%)

F3/4

23

6668

13

44

68

61117n= 19 153231

Patients with F3/4 did better with full yr of therapy vs response-guided therapy


Subanalysis of Phase III Boceprevir Trials: IL28B as a Predictor of Response SPRINT-2: GT1 treatment-naive RESPOND-2: GT1 relapsers and

partial responders to pegIFN/RBV

Poordad F, et al. EASL 2011. Abstract 12. Graphics used with permission.

PR48BOC RGTBOC/PR48

100

80

60

40

20

0

SV

R (

%)

100

80

60

40

20

0

SV

R (

%)

CC* CT TT

6377

4455

67103

82115

2342

2644

82

6571

5559

5064

33116

1037

78

28 27

*~ 90% eligible for short duration therapy.

CC* CT TT

2228

1722

3862

4866

611

1318

7977

6173

613

529

510

46

17

55

72

50

80

*~ 80% eligible for short duration therapy.

n/N =

n/N =


Poordad F, et al. EASL 2011. Abstract 12. Graphics used with permission.

100

80

60

40

20

0

Un

det

ecta

ble

HC

V R

NA

by

Wee

k 8*

(%

)

SPRINT-2 RESPOND-2

CCCT + TT

*Decision point for short vs long treatment duration with RGT.

89

52

82

51

118132

158304

4150

80156

Subanalysis of SPRINT-2 and RESPOND-2: IL28B as a Predictor of Response IL28B genotype a predictor of eligibility for shortened therapy


Efficacy of Boceprevir When PegIFN alfa-2a Used as Backbone With RBV Randomized phase III trial with identical inclusion criteria to RESPOND-2 Previous nonresponders or relapsers randomized to

– 4-wk lead-in, then 44 wks placebo + pegIFN alfa-2a/RBV (n = 67), or

– 4-wk lead-in, then 44 wks BOC + pegIFN alfa-2a/RBV (n = 134)

Flamm S, et al. EASL 2011. Abstract 1366. Graphic used with permission.

SVR by Historical Response to Previous Treatment100

80

60

40

20

0

SV

R (

%)

PegIFN alfa-2a/RBV

BOC + pegIFN alfa-2a/RBV

Level observed in

RESPOND-2 trial using pegIFN alfa-2b

Previous Nonresponder Previous Relapser

5

47

28

70

21

64

Overall86/134 14/67 17/36 1/20 69/98 13/47n/N =

21

66

7

52

29

75

Novel HCV Agents in Treatment-Naive Patients


SILEN-C1: BI 201335 + PegIFN/RBV in GT1 Treatment-Naive Patients BI 201335: an inhibitor of HCV NS3-4A protease Placebo-controlled, double-blind phase IIb trial

Sulkowski M, et al. EASL 2011. Abstract 60.

*PegIFN alfa-2a 180 μg/wk + RBV 1000-1200 mg/day. †On Day 1, loading dose of BI 201335 given in all BI 201355 arms (double daily dose: 240 or 480 mg).

Treatment-naive patients infected with GT1 HCV

(N = 429) BI 201335 240 mg/day† + PR*(n = 143)

BI 201335 120 mg/day† + PR*(n = 69)

Week 24

BI 201335 240 mg/day† + PR* (n = 146)


Randomized 1:2:2:1

Lead-in*(n = 146)

Lead-in*(n = 69)

Day 4

PR*

Stop treatment; follow-up only

PR*

PR*

Week 48

eRVR

No eRVR


SILEN-C1: BI 201335 + PegIFN/RBV in GT1 Treatment-Naive Patients Higher SVR rates in BI 201335

240 mg QD arms No benefit of extended treatment in

those with eRVR

Sulkowski M, et al. EASL 2011. Abstract 60. Graphics used with permission.

40/71 49/69 103/142 118/142

SVR

Pat

ien

ts (

%)

56

71 7383

100

80

60

40

20

0

P = .081

P = .021

P = .001

PegIFN/RBV 120 mg QD LI240 mg QD LI 240 mg QD 240 mg QD LI

240 mg QD

SVR in eRVR Patients Randomized to 24 or 48 Wks of PegIFN/RBV

40/49 53/57 46/48 53/59

24 Wks

8293 96

90100

80

60

40

20

0

P = .051

48 Wks

P = .743

Pat

ien

ts (

%)

LI, arm containing lead-in phase.

n/N = n/N =


SILEN-C1: BI 201335 + PegIFN/RBV in GT1 Treatment-Naive Patients

Sulkowski M, et al. EASL 2011. Abstract 60. Graphic used with permission.

Safety, % Control Arm

(n = 71)

240-mg BI 201335(n = 149)

240-mg BI 201335 With Lead-in

(n = 138)

120-mg BI 201335 With Lead-in

(n = 68)

Serious adverse event 4.2 12.8 15.9 11.8

Discontinuation due to adverse events 1.4 5.4 11.6 4.4

Rash 0 3.4 3.6 0

Photosensitivity 0 0.7 0 0

Jaundice 0 0.7 0 0

Adverse events*

Nausea 19.7 44.3 47.1 25.0

Diarrhea 18.3 26.8 31.9 13.2

Vomiting 5.6 22.8 18.1 20.6

Pruritus 16.9 37.6 34.8 32.4

Rash 16.9 26.8 28.3 20.6

• Moderate 2.8 14.1 8.0 2.9

• Severe 0 4.0 3.6 0

Jaundice† 1.4 24.2 18.8 5.9

*Events ≥ 10% relative to control.†No severe cases.


ESSENTIAL: Alisporivir + PegIFN/RBV in GT1 Treatment-Naive Patients Alisporivir: oral inhibitor of cyclophilin that acts as host-targeted antiviral

– Modified form of cyclosporin A with enhanced cyclophilin binding but no immunosuppressive activity

– Targets host cyclophilin A required for HCV replication

Placebo-controlled, double-blind phase IIb trial

Flisiak R, et al. EASL 2011. Abstract 4.

Treatment-naive patients with

genotype 1 HCV

(N = 288)

Alisporivir* + PR†

(n = 72)


(n = 72)


(n = 71)

Week 48

Placebo + PR†

(n = 73)

Week 24

RGT: alisporivir + PR‡ 24-wk follow-up

*Alisporivir dosed at 600 mg BID for first wk, then 600 mg QD thereafter. †PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/ day. ‡Patients with RVR (ie, HCV RNA ≤ 10 IU/mL at Week 4) treated for 24 wks; patients without RVR treated for 48 wks.


ESSENTIAL: Alisporivir + PegIFN/RBV in GT1 Treatment-Naive Patients

Improved SVR rates with alisporivir vs pegIFN/RBV, regardless of IL28B GT

Transient hyperbilirubinemia associated with initial loading dose of alisporivir

– 4.2% had total bilirubin ≥ 5 x ULN; resolved to < 5 x ULN by Week 4

Flisiak R, et al. EASL 2011. Abstract 4. Graphic used with permission.

100

80

60

40

20

0

Pat

ien

ts (

%)

LOQ < 25 IU/mL

15

44* 42*

53*

PR Alisporivir 48

Alisporivir-RGT

Alisporivir24

n/N = 39/73 54/72 49/71 34/72

100

80

60

40

20

0

Pat

ien

ts (

%)

55

7669*

53†

PR Alisporivir 48

Alisporivir-RGT

Alisporivir24

n/N = 39/73 54/72 49/71 34/72

P = .008RVR (< LOQ) SVR

*P = .084 vs PR (ITT). †P = .058 vs alisporivir-RGT (ITT).

*P < .02 vs PR (ITT)


BMS-790052: NS5A replication complex inhibitor

BMS-790052 dosed at 3, 10, or 60 mg QD or placebo, each with pegIFN/RBV for 48 wks

– High rates of SVR with BMS-790052 dosed at 10 or 60 mg QD

BMS-790052 in Tx-Naive GT1 Patients:12-Wk Posttx Analysis of Phase IIa Trial

Safety outcomes with BMS-790052 similar to pegIFN/RBV + placebo

– No incremental hematologic, dermatologic, or hepatic toxicities

Pol S, et al. EASL 2011. Abstract 1373. Graphic used with permission.

RVRSVR12

Su

bje

cts

(%

)*

100

80

60

40

20

05/12 5/12 11/12 11/12 1/12 3/1210/12 10/12

3 mg 10 mg

BMS-790052 (QD)

60 mg Placebo

*Intent to treat analysis.RVR, undetectable (< 10 IU/mL) HCV RNA at Week 4.


JUMP-C Interim Analysis: Mericitabine + PegIFN/RBV in Tx-Naive GT 1/4 Patients Placebo-controlled, double-blind phase IIb trial

Mericitabine (formerly RG7128) a nucleoside inhibitor of HCV NS5B RNA polymerase

Week 36 interim analysis, patients randomized to 1 of 2 groups:

– Mericitabine 1000 mg BID + pegIFN/RBV response-guided therapy (n = 81): triple therapy for 24 wks, then follow-up (if eRVR*) or 24 wks of pegIFN/RBV (if no eRVR)

– PegIFN/RBV for 48 wks (n = 85)

eRVR* 60% (n = 49) in mericitabine arm

– SVR12 in 76% of these patients

Pockros P, et al. EASL 2011. Abstract 1359. *HCV RNA undetectable Weeks 4-22.

63

89 91

14

5162

0

20

40

60

80

100

Week 4 Week 12 Week 24

Mericitabine + pegIFN/RBV(n = 81)

PegIFN/RBV(n = 85)

Un

det

ecta

ble

HC

V R

NA

(%

)

n = 51 72 4312 5374


ZENITH Week 12 Interim Analysis: VX-222 + Telaprevir ± PegIFN/RBV in GT1 Tx Naive Parallel-group, dose-ranging phase II study

*A fifth arm assessing VX-222 400 mg QD + telaprevir 1125 mg BID + RBV currently accruing.†PegIFN 180 µg/wk + weight-based RBV 1000-1200 mg/day.

Treatment-naive patients with

chronic GT1 HCV infection*

(N = 106)

VX-222 400 mg BID + Telaprevir 1125 mg BID(n = 29)

VX-222 100 mg BID + Telaprevir 1125 mg BID + PR†

(n = 29)

VX-222 400 mg BID + Telaprevir 1125 mg BID + PR†

(n = 30)

Week 12

VX-222 100 mg BID + Telaprevir 1125 mg BID(n = 18)

PR for 12 wks if HCV RNA detectable at Weeks 2 or 8†

Week 36‡Stratified by GT (1a/unknown vs 1b) Week 24

Di Bisceglie A, et al. EASL 2011. Abstract 1363.

Stop tx if HCV RNA undetectable at Weeks 2 and 8†

PR for 12 wks if HCV RNA

detectable at Weeks 2 or 8†

Stop tx ifHCV RNA

undetectable at Weeks 2 and 8†


No virologic breakthrough in quad-therapy arms

Virologic breakthrough common in VX-222/TVR dual-therapy arms (17% to 31%)

– Both dual regimens stopped prematurely per protocol

HC

V R

NA

Un

det

ecta

ble

(%

)

2217

0 0

24

59

1424

38

86

38

83

57

87

50

90

0

20

40

60

80

100

Week 2 Week 4 Weeks 2 & 8* Week 12

VX-222 100 mg + telaprevir (n = 18)

VX-222 400 mg + telaprevir (n = 29)

VX-222 100 mg + telaprevir + PR (n = 29)

VX-222 400 mg + telaprevir + PR (n = 30)

Di Bisceglie A, et al. EASL 2011. Abstract 1363.

ZENITH Week 12 Interim Analysis: VX-222 + Telaprevir ± PegIFN/RBV in GT1 Tx Naive

*Indicates patients eligible for shortened therapy.


EMERGE Week 12 Results: PegIFN Lambda vs PegIFN alfa-2a in GT1-4 Tx-Naive Pts Phase IIb trial


Interferon-naive pts

(N = 526)

PegIFN alfa-2a 180 μg/wk + RBV*(n = 133)

PegIFN lambda 120 μg/wk + RBV(n = 128)


Week 24 genotypes 2,3Week 48 genotypes 1,4Genotyping at baseline


*RBV dosed at 800 mg/day for genotype 2/3 and 1000-1200 mg/day for genotype 1/4 patients.


Zeuzem S, et al. EASL 2011. Abstract 1360. Graphics used with permission.

PegIFN dose reductions: 18.8% with pegIFN α-2a vs 5.9% with pegIFN λ (12.7% with highest pegIFN λ dose)

RBV dose reductions/stoppages: 20.3% with pegIFN α-2a vs 8.7% with pegIFN λ

PegIFN λ associated with fewer hematologic adverse events, lower incidence of myalgia, pyrexia, arthralgia, chills, rash

– Higher incidence of direct hyperbilirubinemia higher with pegIFN λ

– Elevated ALT/AST more common with highest-dose pegIFN λ

Undetectable HCV RNA at Week 12 (cEVR): HCV Genotypes 1, 4

55.0* 55.9* 56.3*

37.9

HC

V R

NA

Un

de

tec

tab

le(%

of

pa

tie

nts

± 9

5%

CI) 100

80

60

40

20

0120 µg 180 µg 240 µg PegIFN

alfa-2a

n = 100 102 103 103

*P < .05 vs pegIFN alfa-2a

Undetectable HCV RNA at Week 12 (cEVR): HCV Genotypes 2, 3

90.0 96.683.3 86.2100

80

60

40

20

0n = 30 29 30 29

PegIFN Lambda

120 µg 180 µg 240 µg PegIFNalfa-2a

PegIFN Lambda

EMERGE Week 12 Results: PegIFN Lambda vs PegIFN alfa-2a in GT1-4 Tx-Naive Pts


PROTON: PSI-7977 + PegIFN/RBV in GT2/3 or GT1 Treatment-Naive Patients PSI-7977: pyrimidine nucleotide

analog polymerase inhibitor

PROTON: phase IIb study of PSI-7977–based triple therapy in treatment-naive patients

– SVR12 in 96% of GT2/3 patients (N = 25) treated with PSI-7977 400 mg QD + pegIFN/RBV for 12 wks (ITT analysis)[1]

– 12-wk interim analysis in GT1 compares PSI-7977 at 200 mg QD or 400 mg QD vs placebo, all with pegIFN/RBV (ITT analysis)[2]

Extended RVR in 95% of GT1 patients receiving PSI-7977[2]

1. Lalezari J, et al. EASL 2011. Abstract 61. 2. Nelson D, et al. EASL 2011. Abstract 1372. Graphic used with permission.

100

80

60

40

20

0Week 2 Week 4 Week 12

HC

V R

NA

< L

OD

(%

)

PSI-7977 400 mg + pegIFN/RBV (n = 47)PSI-7977 200 mg + pegIFN/RBV (n = 48)Placebo + pegIFN/RBV (n = 26)

10092

62

9898

19

7177

NR


NUCLEAR: Phase I Study of 14 Days QD PSI-7977 + PSI-938 in Tx-Naive GT1 HCV PSI-938: purine nucleotide analog with complementary mechanism, activity to PSI-7977

Lawitz E, et al. EASL 2011. Abstract 1370. Graphic used with permission.

HCV RNA Change From Baseline*

Day 7 Day 14 Total

< LOD, n Median (Q1, Q3) < LOQ, n < LOD, n Median (Q1, Q3) < LOD, %

Cohort 1 2 -4.5 (-4.3, -4.7) 5 4 -5.2 (-4.8, -5.8) 50

Cohort 2 2 -4.6 (-4.2, -5.0) 8 8 -5.2 (-4.8, -5.5) 100

Cohort 3 4 -4.7 (-4.3, -4.8) 8 7 -5.0 (-4.6, -5.4) 88

Cohort 4 1 -4.4 (-4.2, -4.8) 8 5 -5.0 (-4.7, -5.3) 88†

HC

V R

NA

Ch

an

ge

Fro

m

Ba

se

lin

e (

log

10 I

U/m

L)

*Cumulative total of individuals whose HCV RNA reached < LOD as a result of the study treatment. †Includes 2 additional subjects whose HCV RNA reached < LOD on Day 16. LOD < 15 IU/mL. Median baseline HCV RNA 6.9 in cohort 1, 6.3 in cohort 2, 6.3 in cohort 3, 6.2 in cohort 4.

Cohort 1: PSI-938 Days 1-14

Cohort 2: PSI-938 Days 1-7 → PSI-938 + PSI-7977 Days 8-14

Cohort 3: PSI-7977 Days 1-7 → PSI-938 + PSI-7977 Days 8-14

Cohort 4: PSI-938 + PSI-7977 Days 1-14

0-1-2-3-4-5-6-7

20 144 6 8 10 12Days

PSI-938 dosed at 300 mg QD, PSI-7977 dosed at 400 mg QD.


PILLAR: Impact of IL28B and IP-10 in GT1 Tx-Naive Patients Receiving TMC435 + PR Phase IIb study of TMC435 combined with pegIFN/RBV

In patients treated with placebo + pegIFN/RBV, IP-10 level and IL28B genotype predictive of response, most notably at Week 24

– Best responses in those with lower IP-10 levels, CC IL28B genotype

Aerssens J, et al. EASL 2011. Abstract 11. Graphic used with permission.

Virologic Response*: Placebo + PegIFN/RBV

100

80

60

40

20

0

IP-10

IL28

B

< 600 pg/mL600 pg/mL

Week 4 Week 24

TT

CT

CC

100

80

60

40

20

0

IP-10

IL28

B


TT

CT

CCPat

ien

ts (

%)

20 5

17

0

50

77

40

100

*HCV RNA < 25 IU/mL.


100

PILLAR: Impact of IL28B and IP-10 in GT1 Tx-Naive Patients Receiving TMC435 + PR High response rates with TMC435 + pegIFN/RBV regardless of

IP-10 level or IL28B genotype

Highest rates of response in difficult-to-treat patients (low IP-10, TT IL28B genotype) in those treated with TMC435 150 mg QD

Aerssens J, et al. EASL 2011. Abstract 11. Graphics used with permission.

Virologic Response*:TMC435 150 mg QD + PegIFN/RBV

Virologic Response*:TMC435 75 mg QD + PegIFN/RBV

Week 4

100

80

60

4020

0

IP-10

IL28

B


TTCT

CCPat

ien

ts (

%)

N=1

86100

10010093

67

Week 24

100

80

60

4020

0

IP-10

IL28

B


TTCT

CC

96100

100100

67

Week 4

100

80

60

4020

0

IP-10

IL28

B


TT

CTCCP

atie

nts

(%

)

N=1

100

Week 24

100

80

60

4020

0

IP-10

IL28

B


TTCT

CC

N=1

100 90100100

83

95

77

9596

100

100

*HCV RNA < 25 IU/mL

Novel HCV Agents in Treatment-Experienced Patients


BMS-790052 + BMS-650032 ± PegIFN/RBV for 24 Wks in GT1 Null Responders

In dual therapy arm, 2/2 GT1b vs 2/9 GT1a patients reached SVR12 and SVR24

No viral breakthrough with quadruple therapy

BMS-790052 and BMS-650032 alone or with pegIFN/RBV generally well tolerated

Lok A, et al. EASL 2011. Abstract 1356.

BMS-790052 60 mg QD + BMS-650032 600 mg BID

(n = 11)Phase IIa study: GT1 null responders*

with HCV RNA ≥ 105 IU/mL

(N = 21)

Follow-up 48 wksBMS-790052 60 mg QD +

BMS-650032 600 mg BID +PegIFN/RBV

(n = 10)

Week 24Stratified by HCV subgenotype

(1a vs 1b)

*< 2 log10 IU/mL decline in HCV RNA with ≥ 12 wks of pegIFN/RBV.

†1 patient not achieving SVR24 had HCV RNA < 25 IU/mL at EOT and undetectable on retesting at Day 35 of follow-up.

Undetectable HCV RNA, % (n)

BMS-790052 +BMS-650032

(n = 11)

BMS-790052 +BMS-650032 + PR

(n = 10)

RVR 64 (7) 60 (6)

SVR12 36 (4) 100 (10)

SVR24 36 (4) 90† (9)


SILEN-C2: BI 201335 + PegIFN/RBV in GT1 PegIFN/RBV Tx-Experienced Patients Phase IIb, double blind, placebo-controlled trial

Sulkowski M, et al. EASL 2011. Abstract 66.

GT1 previous nonresponders

(N = 288)

PR* + BI 201335 240 mg BID

PR* + BI 201335 240 mg QD†

Week 24

PR* + BI 201335 240 mg QD†‡

(n = 76)

Randomized 1:1:2

*PegIFN alfa-2a 180 μg/wk + RBV 1000-1200 mg/day. †Patients with eRVR at Week 24 rerandomized 1:1 to 24 or 48 total wks of pegIFN/RBV.

Lead-in*(n = 70)

Day 4

PR*

PR*

PR*

Week 48

Off-tx follow-upLead-in*(n = 142)


SILEN-C2: BI 201335 + PegIFN/RBV in GT1 PegIFN/RBV Tx-Experienced Patients

Sulkowski M, et al. EASL 2011. Abstract 66. Graphics used with permission.

SVR in eRVR Pts by Duration of PegIFN/RBV

Null response: < 1 log10 maximum HCV RNA reduction any time during treatment;partial response: > 1 log10 maximum HCV RNA reduction but never undetectable (with a sensitive assay).

100

80

60

40

20

0

Pat

ien

ts (

%)

Overall Partial Responders

Null Responders

39/142 22/70 16/54 10/24 12/57 11/38

2731 30

42

21

31/76 13/26 14/40

41

50

3529

240 mg QD 240 mg QD LI240 mg BID LI

240 mg QD LI 24 wks240 mg QD LI 48 wks100

80

60

40

20

0

Pat

ien

ts (

%)

Overall

12/30 21/29

40

P = .018

72

SVR According to Previous Response Category

n/N = n/N =


SILEN-C2: BI 201335 + PegIFN/RBV in GT1 PegIFN/RBV Tx-Experienced PatientsOutcome, % 240-mg QD

BI 201335(n = 76)

240-mg QDBI 201335

With Lead-in(n = 141)

240-mg BIDBI 201335

With Lead-in(n = 69)

Serious adverse event 14.5 14.2 27.5

Discontinuation due to adverse events 3.9 5.7 23.2

Rash 1.3 0 14.5

Photosensitivity 0 0 1.4

Jaundice 0 0.7 1.4

Adverse events*

Nausea 52.6 48.2 63.8

Diarrhea 31.6 31.9 39.1

Vomiting 22.4 17.0 31.9

Rash 27.6 34.0 42.0

• Severe 1.3 0.7 5.8

Jaundice† 21.1 19.0 41.4

Sulkowski M, et al. EASL 2011. Abstract 66. Graphic used with permission.*Events ≥ 10% relative to control. †No severe cases.


ASPIRE 24-Wk Interim Analysis: TMC435 + PegIFN/RBV in Tx-Experienced GT1 HCV


*PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.

24-wk follow-up

Phase IIb study: Patients with

chronic GT1 HCV who failed previous

pegIFN/RBV

(N = 463)

TMC435 150 mg QD + PR*(n = 65)

TMC435 100 mg QD + PR*(n = 65)

TMC435 150 mg QD + PR*(n = 68)

Week 12

TMC435 100 mg QD + PR*(n = 66)

Week 48

TMC435 100 mg QD + PR*(n = 68)

TMC435 150 mg QD + PR*(n = 65)


Week 24: current analysis

•Placebo + PR*

•Placebo + PR*

•Placebo + PR*

•Placebo + PR*

Stratified by genotype (1a vs 1b vs other), previous response (relapse vs partial response vs null response

in 2:2:1 ratio)


Results of ASPIRE 24-Wk Interim Analysis in Previous Null Responders Significantly higher rates of undetectable HCV RNA with TMC435-containing

arms vs pegIFN/RBV alone

– Undetectable HCV RNA at Week 24 in 70% to 87% of previous null responders, 83% to 89% of previous partial responders, 92% to 96% of previous relapsers

Safety and tolerability of TMC435-based regimens comparable to pegIFN/RBV apart from increase in influenzalike symptoms and pruritus


Rates of Undetectable HCV RNA in Previous Null Responders to PegIFN/RBV

10080

60

4020

0

Week 4

Pat

ien

ts (

%)

TMC 100 mgGroups(n = 47)

TMC 150 mgGroups(n = 51)

PR48(n = 16)

4036

100

8060

4020

0

Week 24

Pat

ien

ts (

%)

TMC 100 mg12 Wks(n = 14)

TMC 100 mg

24 & 48 WksCombined

(n = 28)

PR48(n = 9)

7470 7087

45

TMC 150 mg12 Wks(n = 17)

TMC 150 mg

24 & 48 WksCombined

(n = 31)

0

Hepatitis B


1285 HBsAg-positive individuals with 19,321 PYs follow-up

– 111 incident HCC cases

Persistent HBV DNA as Predictor for HCC

Liu J, et al. EASL 2011. Abstract 68. Graphic used with permission.

Factor HCC Incidence Rate per

100,000 PYs

Multivariable-Adjusted HR

for HCC*(95% CI)

P Value

HBeAg seroclearance†

No 1123.9 1.0

Yes 729.4 0.85 (0.53-1.36) .49

HBV DNA decreased to undetectable

No 669.2 1.0

Yes 94.3 0.28 (0.08-0.98) .04

HBsAg seroclearance

No 609.7 1.0

Yes 78.1 0.73 (0.09-6.25) .77

*Adjusted for age, sex, smoking, drinking, baseline HBV DNA, and baseline ALT.†HBeAg-positive patients only (N = 439).

0.12

0.10

0.08

0.06

0.04

0.02

0

Cu

mu

lati

ve H

CC

Inci

den

ce

0 2 4 6 8 10 12 14 16 18

Yrs

HBV DNA persistently detectable

HBV DNA seroclearance

1.5%

11.1%


NEPTUNE: On-Treatment HBsAg Level as Marker of Response to PegIFN HBeAg-positive patients: pegIFN alfa-2a 180 µg/wk for 48 wks

– HBsAg analyzed at baseline and every 12 wks

Gane E, et al. EASL 2011. Abstract 69. Graphic used with permission.

HBsAg levels (IU/mL) at Wk 12

100

80

60

40

20

0

Res

po

nse

6 M

os

Po

sttr

eatm

ent

(%)

P < .0001

P = .0004

19%27%

54%

HBeAg Seroconversion

HBV DNA < 2000 IU/mL

HBsAg Clearance

< 1500(n = 31)

< 1501-20,000(n = 62)

> 20,000(n = 21)

P = .2866

58

42

0

52

31

0 0 010

HBsAg levels (IU/mL) at Wk 24

100

80

60

40

20

0

P = .0003

P = .0015

14%

40%

46%

HBeAg Seroconversion

HBV DNA < 2000 IU/mL

HBsAg Clearance

< 1500(n = 46)

< 1501-20,000 (n = 52)

> 20,000 (n = 16)

P = .3819

57

35

0

54

19

0 0 07


NEPTUNE: On-Treatment HBsAg as Marker of Response to PegIFN HBsAg < 20,000 IU/mL identified as key

marker of response

HBsAg > 20,000 IU/mL at Week 12 or 24 predicts lack of HBeAg seroconversion

– Negative predictive value: 100%

Combination of ALT level and HBsAg decline improves positive predictive value

Gane E, et al. EASL 2011. Abstract 69. Graphic used with permission.

100

80

60

40

20

0HB

eAg

Se

roco

nve

rsio

n

6 M

os

Po

sttr

eatm

ent

(%)

47

0 0

45

Week 12 Week 24

HBsAg (IU/mL)

(n = 93)

< 20,000

(n = 21)

> 20,000

(n = 98)

< 20,000

(n = 16)

> 20,000

100

80

60

40

20

0HB

eAg

Se

roco

nve

rsio

n

6 M

os

Po

sttr

eatm

ent

(%)

46

0 0

45

1-2 x ULN > 2 x ULN

HBsAg Levels at Week 12

< 1500 IU/mL 1500-20,000 IU/mL> 20,000 IU/mL

68

31

ALT


Does IL28B GT Predict HBsAg Clearance? Primarily HBeAg-Negative Population HBsAg-positive patients treated

with IFN or pegIFN for 12-24 mos (N = 151)

– 127 HBeAg negative

– 24 HBeAg positive

– All white, HBV genotype D

Response defined as HBsAg loss and anti-HBs seroconversion

– Mean posttreatment follow-up: 24 mos (range: 12-52)

No significant association observed

Mangia A, et al. EASL 2011. Abstract 1331. Graphic used with permission.

P = .28

IL28B Genotype and HBsAg Clearance

100

80

60

40

20

0IL

28B

Dis

trib

uti

on

(%

)

HBsAg Clearance

No HBsAg Clearance

5044

6

35

47

18

CCCTTT


Does IL28B GT Predict HBsAg Clearance? HBeAg-Positive Population HBeAg-positive patients treated with IFN (n =

14) or pegIFN alfa-2a or 2b ± LAM (n = 191)

– 65% Asian, 29% white

– HBV GT: 47% C, 20% B, 13% A, 13% D

IL28B genotyping at SNPs rs12980275 and rs12979860

– Only rs12980275 reported

– AA/AG/GG nomenclature with this SNP essentially equivalent to common CC/CT/TT nomenclature with rs12979860

Median follow-up: 173 wks (IQR: 108-356)

IL28B independently predicted HBeAg seroconversion and HBsAg seroclearance

Sonneveld MJ, et al. EASL 2011. Abstract 71.Graphics used with permission.

HR for AA vs AG/GG: 3.47 (1.04-13.48)

HR for AA vs AG/GG*: 2.14 (1.14-4.31)

*Adjusted for HBV genotype and baseline ALT and HBV DNA

100

80

60

40

20

0Cu

mu

lati

ve

Pro

ba

bil

ity

of

HB

eA

g S

ero

co

nv

ers

ion

0 48 96 144 192 240 288 336Wks

AA genotype

AG/GG genotype

P = .018

10

8

6

4

2

0

HB

sA

g S

ero

cle

ara

nc

e

0 48 96 144 192 240 288 336Wks

AA genotype

AG/GG genotype

P = .042

Advanced Liver Disease


Rifaximin for Maintenance of Remission From Overt HE

1. Bass NM, et al. N Engl J Med. 2010;362:1071-1081. 2. Mullen K, et al. EASL 2011. Abstract 109.

Patients with recurrent HE (≥ 2 overt episodes

within 6 mos of screening) and Conn

score 0 or 1, currently in remission

(N = 299)

Rifaximin 550 mg BID*(n = 140)

Placebo*(n = 159)

Mo 6

*Concomitant lactulose permitted. †≥ 2 overt HE episodes within 12 mo of screening and Conn score ≤ 2.

Randomized-controlled trial[1] Open-label maintenance[2]

n = 82†

n = 70†

n = 170 new pts†Rifaximin 550 mg BID*

(n = 322)


Rifaximin for Maintenance of Remission From Overt HE Rifaximin provided long-term

protection from HE recurrence Reduced rate of hospitalizations

in the long term with rifaximin

1. Bass NM, et al. N Engl J Med. 2010;362:1071-1081. 2. Mullen K, et al. EASL 2011. Abstract 109.Graphics used with permission.

HE

Bre

ak

thro

ug

h E

ve

nts

/PE

Y

2

1

0

1.6

0.6*

0.4*

0.2*0.3*

Long-term open-label F/U

Rifaximin RCT (n = 140)Placebo crossover (n = 82)Continuing rifaximin (n = 70)New rifaximin (n = 252)

Exposure (PEY)Events/PEY

461.59

500.62

1340.40

1470.24

3420.30

*P < .0001 vs placebo.PEY, person exposure yrs.

*Includes 140 patients in rifaximin group from RCT, 82 patients from placebo group in RCT who switched to open-label rifaximin maintenance, and 170 patients who newly entered the study during the open-label maintenance phase.†P = .0051 vs placebo‡P < .001 vs placebo.

RCT All RifaximinPatients*(n = 392)

Rifaximin(n = 140)

Placebo(n = 159)

PEY 50 46 510

Hospitalizations due to HE

n (%) 15 (11) 33 (21) 109 (23)

Events/PEY

0.30† 0.72 0.21‡

Placebo RCT (n = 159)

Patients Treated With Rifaximin


Impact of Adrenal Dysfunction in Cirrhotic Patients With Ascites Corticotropin stimulation test performed in a series of 85 consecutive

cirrhotic patients with ascites

– Adrenal dysfunction: change in cortisol < 9 µg/dL and/or peak cortisol < 18 µg/dL

– Patients followed until liver transplantation or death (median: 198 days)

39% had adrenal dysfunction

Survival significantly poorer in pts with adrenal dysfunction (P = .02)

Predictors of mortality (multivariate analysis)

– Adrenal dysfunction: HR: 2.1 (95% CI: 1.1-4.0; P = .03)

– PRA > 4 ng/mL/hr: HR: 2.1 (95% CI: 1.1-4.0; P = .03)

– MELD score > 18: HR: 2.0 (95% CI: 1.1-3.5; P = .02)

Elia C, et al. EASL 2011. Abstract 106.


Does Moderate Hypothermia Prevent Brain Edema in Acute Liver Failure?* Prospective, randomized, controlled, multicenter trial

Patients with acute liver failure and imminent brain edema and planned intracranial pressure monitoring

– Standard medical therapy: n = 33

– Median core temperature: 36.7°C

– Standard medical therapy + 3 days moderate hypothermia: n = 21

– Median core temperature: 33.2°C

Similar rates of intracranial hypertension: 57% with MH vs 45% for control (P = .58)

Similar rates of mortality: 48% with MH vs 58% for control (NS)

Larsen, et al. EASL 2011. Abstract 56.

*Slide content based only on abstract data.


Radioembolization With 90Y-Resin Microspheres for Unresectable HCC Multicenter patient series: 82% male, 79% cirrhotic, mean age: 64.5 yrs

HCC etiology: HBV (13%), HCV (44%)

Previous procedures: surgical (n = 61), percutaneous ablation (n = 29), intra-arterial (n = 98)

Median survival

– 1 yr: 52.8%

– 2 yrs: 28.1%

– 3 yrs: 15.9%

Median survival according to BCLC stage (P < .001)

– BCLC stage A (n = 52): 24.4 mos

– BCLC stage B (n = 87): 16.9 mos

– BCLC stage C (n = 183): 10.0 mos

– BCLC stage D (n = 3): 5.2 mos

Sangro B, et al. EASL 2011. Abstract 80.


Sorafenib + Percutaneous RFA of HCC and PVTT vs Sorafenib Alone Child-Pugh A cirrhotic patients (N = 79) with untreated HCC (single tumor ≤ 6.5 cm or 3

nodules ≤ 5 cm) and portal vein tumor thrombus (PVTT)

Sorafenib 800 mg/day started soon after RFA/diagnosis

Combination treatment significantly improved survival (P < .001)

Giorgio A, et al. EASL 2011. Abstract 1368.

Survival, % Sorafenib Sorafenib + RFA

1 yr 37 60

2 yrs 0 35

3 yrs Not reached 26


Resection of HCC Followed by Salvage Transplantation* 1998-2008: 114 transplantable patients with good liver function and

HCC within Milan criteria underwent resection

– Transplantation offered if recurrence of chronic liver disease

Recurrence occurred in 80% of resected cases

– Only 54% of patients went on to salvage transplantation

Risk factors for recurrence beyond Milan criteria (multivariate analysis)

– Poor differentiation, presence of vascular invasion, older than 60 yrs of age

Risk factors for missing opportunity of LT after recurrence (univariate analysis)

– Presence of F4, tumor size > 3 cm, R1 surgical margin

Fuks D, et al. EASL 2011. Abstract 57.



Molecular Signature for Diagnosis, Prognosis of HCC* Whole-genome profiles of frozen samples analyzed (N = 110)

– HCC of various etiologies, HCA, FNH, cirrhosis, and normal liver tissues

– 96 genes analyzed as potential markers of

– Benign liver tumors according to their different pathologic and molecular subtypes, and

– HCC according to prognosis

5-gene predictor associated with overall survival in HCC

– HR: 2.6 (CI: 1.6-4.2; P < .001)

– More significantly associated with overall survival than previous G1-G6 or proliferative-transcriptomic classifications

Nault JC, et al. EASL 2011. Abstract 76.



IL28B as Predictor of Response to HCV Treatment in Recurrence After Transplant* Liver transplantation recipients with HCV recurrence who received ≥ 12 wks of

pegIFN/RBV (N = 132)

– IL28B SNPs rs8099917 and rs12979860 genotyped

– Recipients: peripheral lymphocytes or liver explants

– Donors: liver biopsies immediately after reperfusion of the graft

Patients with favorable donor and recipient IL28B genotypes had highest probability of SVR (79%; P = .001 vs other combinations)

Multivariate analysis: CC genotype of rs12979860 identified as baseline independent predictor of SVR (OR: 4.2; 95% CI: 1.4-12.3; P = .01)

SVR in 85% of recipients with CC genotype and HCV RNA < 6.5 log10 IU/mL vs 23% in patients with CT/TT genotype and HCV RNA > 6.5 log10 IU/mL (P < .001)

Crespo G, et al. EASL 2011. Abstract 30.


Nonviral Hepatitis


(N = 89)

Rosiglitazone ± Metformin or Losartan for Treatment of NASH Randomized, open label: 137 biopsy-

proven NASH patients received

– Rosiglitazone 4 mg BID

– Rosiglitazone 4 mg BID + metformin 500 mg BID

– Rosiglitazone 4 mg BID + losartan 50 mg QD

Improvement in ALT, insulin resistance not correlated with NASH resolution

Caveats: pts were relatively young, majority was white

Less weight gain with metformin vs other groups

Trial halted because of limitations put on use of rosiglitazone in US

Jones FJ, et al. EASL 2011. Abstract 15. Graphics used with permission.

Steatosis: Pre and Posttreatment*

*P value between groups: ≥ .05P value within groups: ≤ .001

3.53.02.52.01.51.00.5

0Rosiglitazone

(n = 26)Rosiglitazone+ Metformin

(n = 28)

Rosiglitazone+ Losartan

(n = 35)

28.0%29.8%

24.9%

(N = 89)Fibrosis: Pre and Posttreatment*

2.0

1.5

1.0

0.5

0Rosiglitazone

(n = 26)Rosiglitazone+ Metformin

(n = 28)

Rosiglitazone+ Losartan

(n = 35)

43.2% 37.1%19.6%

Sta

ge

Act

ivit

y S

core


Mycophenolate Mofetil With Corticosteroids in Autoimmune Hepatitis Chart review: patients with AIH or AIH-overlap syndromes and past or

present use of MMF included (N = 661)

– Efficacy of MMF in pts with azathioprine nonresponse or intolerance

Pronk AMC, et al. EASL 2011. Abstract 23.

AIH Overlap syndrome

AZA Intolerant AZA NonrespondersOverall

Rem

issi

on

on

MM

F (

%)

100

80

60

40

20

0

47

67 63

13

57

Go Online for More CCO Coverage of EASL 2011!

Capsule Summaries of all the key data

Podium to Practice Expert Analysis panel discussion exploring the clinical implications of the most important data from the meeting

clinicaloptions.com/Berlin2011

http://www.clinicaloptions.com/Berlin2011

clinicaloptions.com/hepatitis highlights from berlin 2011 march 30 - april 3, 2011 berlin, germany...

Documents