Clinicaloptions.com/hepatitis Highlights of AASLD 2012 Highlights of AASLD 2012 CCO Official...

clinicaloptions.com/hepatitisHighlights of AASLD 2012

Highlights of AASLD 2012CCO Official Conference Coverage of the 2012 Annual Meeting of the American Association for the Study of Liver Diseases

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November 9-13, 2012Boston, Massachusetts

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Faculty

Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom

Paul Y. Kwo, MDProfessor of MedicineMedical Director of TransplantationDivision of Medicine/Gastroenterology/HepatologyIndiana University School of MedicineIndianapolis, Indiana


Faculty Disclosures

Graham R. Foster, FRCP, PhD, has disclosed that he has received consulting fees and fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, Roche, and Vertex; and grants for research support from Janssen and Roche.

Paul Y. Kwo, MD, has disclosed that he has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Novartis, and Vertex; fees for non-CME services from Bristol-Myers Squibb, Merck, and Vertex; grants for research support from Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Roche, and Vertex.

Hepatitis CCurrent Therapy


OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx-Naive Pts With GT1 HCV Infection Randomized, multicenter, open-label phase III noninferiority trial

Buti M, et al. AASLD 2012. Abstract LB-8.

Treatment-naive

patients with chronic GT1

HCV infection (N = 740)

Telaprevir 750 mg q8h + PegIFN/RBV

(n = 371)

Telaprevir 1125 mg BID +PegIFN/RBV

(n = 369)PegIFN/RBV

Stratified by fibrosis status (F0-F2 vs F3-F4), IL28B

GT (CC, CT, TT) Wk 12 Wk 24 Wk 48

PegIFN/RBVPegIFN/RBV

RVR

NoRVR

Follow-up

PegIFN/RBV

RVR

NoRVR

Follow-up


SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups

Similar safety and tolerability profile in both treatment arms

OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection

Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.

TVR q8h/PRTVR BID/PR

SV

R12

(%

)

0

20

40

60

80

100

CC CT TT

n/N =

87 92

68 68 65 66

92/106

97/105

141/208

139/206

37/57

38/58

F0-2 F3/4

78 81

59 58

209/268

213/264

61/103

61/105

IL28B GT Liver Disease Status


Retrospective Analysis of TVR in Pts With GT1 HCV and Compensated Cirrhosis Retrospective study from single liver transplantation clinic

eRVR: 35% (14/40 pts)

EOT response: 75% (6/8 pts)

Reasons for discontinuation

– SAE (n = 12)

– Lack of viral response (n = 11)

– Pt preference (n = 6)

– Loss of insurance (n = 2)

Gallegos-Orozco JF, et al. AASLD 2012. Abstract 53.

Pat

ien

ts (

%) 62

2216

100

80

60

40

20

0

Comple

ted

Treatm

ent

Discontin

ued

Treatm

ent

On Tre

atment

100

Initi

ated T

VR

+ PegIF

N/RBV

50/50

72

Comple

ted

> 12 W

ks of R

x

n/ N= 36/50

31/50

11/50

8/50


N-CORE: 24 vs 48 Wks of PegIFN alfa-2a + RBV in GT2/3 Patients Without RVR Multicenter, international, randomized, open-label phase

IIIb trial

Cheinquer H, et al. AASLD 2012. Abstract 156.

Tx-naive patients with chronic GT2/3 HCV

infection who initiated pegIFN/RBV therapy and did not achieve RVR but

did achieve EVR(N = 235)*

Continue PegIFN/RBV (n = 93)

Stop therapy; 48-wk follow-up(n = 95)

Stop therapy; 24-wk follow-up

Wk 24 Wk 48 Wk 72

*47 patients dropped out and did not reach randomization at Wk 24.


N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/RBV

Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm

Cheinquer H, et al. AASLD 2012. Abstract 156. Reproduced with permission.

Odds Ratio 0.68 0.63 0.44

95% CI 0.38-1.21 0.35-1.16 0.22-0.89

P Value .1934 .1461 .0231

49/95

57/93

49/95

51/81

49/90

46/63

SV

R24

(%

)

52

ITT (n = 188)

0

20

40

60

80

100

Per Protocol(n = 176)

Study Completer(n = 153)

24-wk pegIFN/RBV48-wk pegIFN/RBV

6152

6354

73

n/N =

Hepatitis C Current Therapy:Anemia Management


Anemia Management in HCV Pts Treated With BOC: Erythropoietin vs RBV Reduction Subanalysis within randomized trial of GT1 HCV therapy–naive pts receiving

4 wks of lead-in, then either 44 wks of triple therapy or RGT (24-44 wks)[1,2]

Pts with Hb ≤10 g/dL* during BOC-based therapy

(N = 500) Erythropoietin 40,000 IU/wk(n = 251)†

RBV Dose Reduction (by 200-400 mg/day)(n = 249)†

Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks

from initiation of lead-in

1. Poordad F, et al. AASLD 2012. Abstract 154. 2. Lawitz E, et al. AASLD 2012. Abstract 50.

*Baseline Hb requirements: 12-15 g/dL for women, 13-15 g/dL for men.†RBV Dose Reduction included 23 pts with cirrhosis; Erythropoietin included 25 pts with cirrhosis.

Secondary anemia management with RBV dose reduction, erythropoietin administration, or transfusion, allowed if Hb ≤ 8.5 g/dL

Patients discontinued if Hb ≤ 7.5 g/dL


SVR Rates With RBV Dose Reduction or Erythropoietin for Anemia Management Similar SVR rates (71%) with both strategies[1,2]

– Similar SVR rates regardless of timing of anemia management, number of RBV dose reductions, or lowest RBV dose received

– Lower SVR rates if < 50% of per protocol total RBV dose received

Higher SVR rate if anemia management initiated with undetectable HCV RNA[2]

1. Poordad F, et al. EASL 2012. Abstract 1419. 2 Poordad F, et al. AASLD 2012. Abstract 154. Reproduced with permission.

SV

R (

%)

178/249

178/251

111/ 129

107/124

67/120

71/ 121 n/N =

100

80

60

40

20

0All Pts Undetectable Detectable

71 71

86 86

56 56

RBV dose reductionErythropoietin


SVR Rates With RBV Dose Reduction or Erythropoietin in Cirrhotics SVR rates similar with each anemia management strategy in both

cirrhotic and noncirrhotic patients

Higher proportion of cirrhotic patients received secondary anemia management (44% vs 26%; P = .009)

RBV dose reduction should be primary strategy for managing anemia, but erythropoietin may be strongly considered as secondary treatment

Lawitz E, et al. AASLD 2012. Abstract 50.

SVR, % (n/N) Noncirrhotic(n = 438)

Cirrhotic(n = 48)

RBV dose reduction 73 (162/221) 57 (13/23)*

Erythropoietin 72 (157/217) 64 (16/25)**P = .5966 for difference between arms among pts with cirrhosis.

HCV/HIV-Coinfected Patients


Study 110: Telaprevir + PegIFN/RBV in GT1 HCV Tx-Naive HCV/HIV Coinfection Multicenter, randomized, double-blind, placebo-controlled phase II trial

Placebo + PegIFN/RBV

Placebo + PegIFN/RBV

PegIFN/RBV(n = 16)

Part B: Stable ARTHCV/HIV-coinfected patients on

stable ART,*CD4+ cell count ≥ 300 cells/mm3,

HIV-1 RNA ≤ 50 copies/mL(N = 47)

Follow-up

Part A: No Current ARTHCV/HIV-coinfected patients,

CD4+ cell count ≥ 500 cells/mm3,

HIV-1 RNA ≤ 100,000 copies/mL(N = 13)

Follow-up

PegIFN/RBV(n = 6)

PegIFN/RBV(n = 7)

TVR† 750 mg q8h +

PegIFN/RBV

PegIFN/RBV(n = 31)

Wk 12 Wk 48WK 72

(SVR24)Wk 60

(SVR12)

TVR† 750 mg q8h +

PegIFN/RBV

Sulkowski MS, et al. AASLD 2012. Abstract 54.

*Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC).†TVR dose increased to 1125 mg q8h with EFV.


Study 110: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients Higher SVR24 rate with TVR-based

therapy No significant drug–drug

interactions with TVR and ART

– TVR plasma levels similar in patients with or without ART

– EFV and ATV/RTV plasma levels similar in patients with or without TVR

No HIV breakthroughs in patients using ART during HCV treatment

Safety and tolerability similar to treatment in patients with HCV monoinfection

Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission.

Telaprevir + PRPlacebo + PR

Overa

ll

Populatio

nNo A

RT

EFV-Bas

ed

ART

ATV-Bas

ed

ART

74 71 69

80

45

33

50 50

0

20

40

60

80

100

28/38

10/22

5/ 7

2/6

11/16

4/ 8

12/15

4/ 8

SV

R24

(%

)

n/N =

Novel DAAs + PegIFN/RBV


ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive Genotype 1 Patients Interim analysis of randomized, open-label phase IIb study with sofosbuvir

(nucleoside polymerase inhibitor)

Treatment-naive,

noncirrhotic patients*(N = 332)

SOF + PegIFN/RBV(n = 52)



Wk 24Wk 12

SOF (n = 75)

SOF + RBV(n = 75)

Hassanein T, et al. AASLD 2012. Abstract 230.

*All infected with GT1 HCV, except for 11 patients with GT4 HCV and 5 with GT6 HCV in 24-wk arm of SOF + pegIFN/RBV.


ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive Genotype 1 Patients SVR12 in ~ 90% patients with 12 or 24 wks of treatment

High rates of SVR12 in genotype 4/6 with 24 wks of treatment

Sofosbuvir well tolerated up to 24 wks

Hassanein T, et al. AASLD 2012. Abstract 230.

EOT SVR12

100

80

60

40

20

0

HC

V R

NA

< L

OD

(%

)

SOF + PR 12 wks

SOF + PR 24 wks

SOF + PR 12 + 12 wks

9890

9992

9991

11 patients (1 in 12-wk group) who attained SVR12 subsequently lost to follow-up

No relapse after SVR12 in any group

GT4 HCV (n = 11)

GT6 HCV (n = 5)

100

80

60

40

20

0

100

82

100 100

11/11 patients with genotype 4 HCV achieved RVR and EOT response

– 2 LTFU without posttreatment data

No relapse after SVR12 in either group

EOT SVR12


ELECTRON: Sofosbuvir, GS-5885, and RBV in Noncirrhotic Pts With GT1 HCV Interim analysis of nonrandomized phase II study with sofosbuvir

(nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor)

SOF + RBV

Wk 12

Treatment naive (n = 25)

SOF + RBV

SOF + GS-5885 + RBV

SOF + GS-5885 + RBV

Null responders (n = 10)

Treatment naive (n = 25)

Null responders (n = 9)

Patients, %

EOT SVR4 SVR12

100 88 84

100 10 10

100 100

100 100*

Gane EJ, et al. AASLD 2012. Abstract 229.

*Data reported for 3 pts only. Data collection ongoing.

No SAEs related to study drugs; AE profile consistent with RBV toxicity profile


ELECTRON: Sofosbuvir in Patients With GT2/3 HCV Interim analysis of nonrandomized phase II study with SOF (nucleoside polymerase inhibitor) ±

GS-5885 (NS5A inhibitor)

SVR, %

Gane EJ, et al. AASLD 2012. Abstract 229. Reproduced with permission.

SOF + PegIFN + RBV

Wk 12

(n = 10)

Wk 8

SOF + PegIFN + RBV

SOF + PegIFN + RBV

SOF + RBV

SOF

SOF + Reduced-Dose RBV (800 mg/day)

SOF + RBV

SOF + PegIFN + RBV

SOF + RBV

100 (SVR24)

100 (SVR24)

100 (SVR24)

100 (SVR24)

60 (SVR8)

60 (SVR24)

64 (SVR12)

100 (SVR24)

68 (SVR12)

SOF + RBV

Wk 4

SOF + RBV

(n = 10)

(n = 9)

(n = 11)

(n = 10)

(n = 10)

(n = 25)

(n = 10)

(n = 25)

Treatment-naive, GT2/3 HCV

(N = 95)

Treatment-experienced, GT2/3 HCV


MATTERHORN: Danoprevir/RTV, Mericitabine, and PegIFN/RBV in GT1 HCV Randomized, open-label phase II trial of RTV-boosted danoprevir (protease

inhibitor), mericitabine (nucleoside polymerase inhibitor), and pegIFN/RBV

Feld JJ, et al. AASLD 2012. Abstract 81.

Noncirrhotic pts withGT1 HCV and previous

partial response to pegIFN/RBV

(N = 151)

Danoprevir/RTV + Mericitabine + RBV* (n = 52)

Danoprevir/RTV + PegIFN/RBV (n = 49)

Wk 24

Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 50)

Danoprevir/RTV + Mericitabine + RBV* (n = 77)

Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 77)

Noncirrhotic pts with GT1 HCV and previous

null response to pegIFN/RBV

(N = 228)Danoprevir/RTV +

Mericitabine + PegIFN/RBV (n = 74)

Wk 48

PegIFN/RBV

*GT1a HCV pts added pegIFN/RBV due to high relapse rates and are excluded from this analysis.


Response rates highest with 4-drug therapy and lowest with pegIFN-free therapy in both cohorts

MATTERHORN: Response to DNV/RTV, MCB, and PegIFN/RBV in GT1 HCV

Higher response with pegIFN-containing regimens in GT1b vs 1a

– Less relapse with addition of MCB

All regimens generally well tolerated

– 3 potentially treatment-related SAEs

– 5 discontinuations due to AEs

Feld JJ, et al. AASLD 2012. Abstract 81. Reproduced with permission.

DNV/RTV + MCB + RBV

DNV/RTV + pegIFN/RBV

DNV/RTV + MCB + pegIFN/RBV

Re

sp

on

se

(%

)

87

EOT0

20

40

60

80

100

SVR12 EOT SVR12

20/23 n/N =

39

9/23

88

28/32

55

17/31

Prior Partial Response Prior Null Response

84

62/74

96

73/76

94

47/50

94

46/49

86

43/50

56

27/48

8/27

SV

R1

2 (

%)

91

Partial

0

20

40

60

80

100

19/21 n/N =

GT1b GT1a

96 100

30

75 73

25/26

30/30

18/24

32/44

Partial

NullNull

Partial

Partial


Daclatasvir and Asunaprevir in GT1 HCV Previous Null Responders AI447-011: randomized, open-label phase IIa study with daclatasvir (NS5A

inhibitor) and asunaprevir (NS3 protease inhibitor)

Lok AS, et al. AASLD 2012. Abstract 79.

Noncirrhotic pts with GT1 HCV and

previous null response to pegIFN/RBV

(N = 101)

Daclatasvir 60 mg QD + Asunaprevir 200 mg BID*

(n = 18)

Daclatasvir 60 mg QD + Asunaprevir 200 mg QD*

(n = 20)

Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + PegIFN/RBV

(n = 20)

Daclatasvir 60 mg QD + Asunaprevir 200 mg QD + PegIFN/RBV

(n = 21)

Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + RBV

(n = 22)

Wk 24Wk 24

*Only pts with GT1b HCV included in dual-therapy arms.


Outcomes With Daclatasvir + Asunaprevir ± PegIFN or RBV in Null Responders High response rates with 4-drug regimen of DCV + ASV

+ pegIFN/RBV

Lower response rates with 2-drug regimen (all GT1b pts)

– Better response with ASV 200 mg BID vs ASV 200 mg QD

SVR data from 3-drug arm not reported due to high rate of virologic breakthrough in GT1a but not in GT1b

– 10 GT1a pts with virologic breakthrough

– All triple-therapy pts offered pegIFN

– No virologic breakthrough with addition of pegIFN

Virologic breakthrough in 8 pts in 2-drug arms but none in 4-drug arm

3 relapses

– 1 with DCV + ASV QD

– 2 with DCV + ASV + PR

All regimens generally well tolerated, with no discontinuations due to toxicity

Lok AS, et al. AASLD 2012. Abstract 79.

9095

HC

V R

NA

< L

LO

Q (

%)

100 100

21/21

EOT0

20

40

60

80

100

SVR24 EOT SVR12

89

70

78

65

20/20

18/20

20/21

16/18

14/20

14/18

13/20

n/N =

DCV + ASV (BID) + PRDCV + ASV (QD) + PRDCV + ASV (BID)DCV + ASV (QD)


PILLAR/ASPIRE: Simeprevir + PegIFN/RBV in Pts With GT1 HCV, F3/4 Fibrosis Subanalysis of randomized, placebo-controlled phase IIb trials of simeprevir (protease

inhibitor) Relatively high SVR24 rates in pts with advanced fibrosis

– In ASPIRE, 4/13 (31%) F4 null responders achieved SVR24

Poordad F, et al. AASLD 2012. Abstract 83. Reproduced with permission.

SV

R24

(%

) 71

PILLAR Naive, F3

0

20

40

60

80

100

5/ 7

15/19

38/68

0/10

24/39

79

4

56 62

ASPIRE Tx Exp’d,F3 + F4

ASPIRE Tx Exp’d,

F4 Only

Relapser0

20

40

60

80

100

0/ 10

17/26

14/21

0/ 3

7/ 21

65

10

67

33

Partial Responder

Null Responder

Placebo + PRSimeprevir 150 mg QD + PR

1/ 10

SVR24 by METAVIR Score SVR24 by Prior IFN Response in Pts With F3/F4

1/ 23

SV

R24

(%

)

n/N = n/N =

Novel DAAs + Ribavirin Interferon-Free Regimens


AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV Interim analysis of randomized, open-label, phase II study with RTV-boosted

ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (nonnucleoside polymerase inhibitor)

Wk 24Wk 12Wk 8

Cohort 1:Treatment-naive GT1 HCV pts

(N = 438)

Kowdley KV, et al. AASLD 2012. Abstract LB-1.

ABT-450/RTV 150/100 mg QD + ABT-267 + ABT-333 + RBV (n = 80)

ABT-450/RTV 150/100 mg QD +ABT-333 + RBV (n = 41)

ABT-450/RTV 100/100 mg QD or 200/100 mg QD + ABT-267 + RBV (n = 79)

ABT-450/RTV 150/100 mg QD +ABT-267 + ABT-333 (n = 79)

ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV (n = 79)

ABT-450/RTV 100/100 mg QD or 150/100 mg QD +ABT-267 + ABT-333 + RBV (n = 80)


AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV Interim analysis of randomized, open-label, phase II study with RTV-

boosted ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (nonnucleoside polymerase inhibitor)

Kowdley KV, et al. AASLD 2012. Abstract LB-1.

Cohort 2:Treatment-exp’d

GT1 HCV pts with previous null response

(N = 133)

ABT-450/RTV 200/100 mg QD + ABT-267 + RBV

(n = 45)

ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV

(n = 45)

ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV

(n = 43)

Wk 24Wk 12


AVIATOR: SVR12 Rates With ABT-450/RTV, ABT-267, ABT-333, and RBV SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV

– 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs

8 wks 12 wks 12 wks

8286

0

20

40

60

80

100

SV

R12

(%

)

96100 100 100 100 100

8496

56 24

79

100

29 12

85

100

52 27

83

96

52 25

96 100

54 25

81

100

26 18

89100

28 17

Observed data (above bar)

ITT (within bar)

n =

81

988888

10089

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1bABT-450ABT-267ABT-333

RBV

ABT-450ABT-333

RBV

ABT-450ABT-267

RBV

ABT-450ABT-267ABT-333


RBV

ABT-450ABT-267

RBV


RBV

Treatment-Naive Patients Null Responders

Kowdley KV, et al. AASLD 2012. Abstract LB-1. Reproduced with permission.


Daclatasvir + Sofosbuvir ± RBV in Treatment-Naive Patients With GT1-3 HCV

Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

Treatment-naive noncirrhotic patients

with GT1 HCV (N = 126)

SOF + DCV (n = 14)

SOF + DCV + RBV (n = 15)

Wk 24

SOF + DCV (n = 41)

Wk 12Wk 1

SOF SOF + DCV (n = 15)

SOF + DCV + RBV (n = 41)

SOF + DCV (n = 14)

SOF + DCV+ RBV (n = 14)

SOF SOF + DCV (n = 16)Treatment-naive

noncirrhotic patients with GT2/3 HCV

(N = 44)

AI444-040: interim analysis of randomized, open-label phase IIa trial of daclatasvir (NS5A inhibitor) and sofosbuvir (nucleotide polymerase inhibitor)


SVR24

Similar high SVR4 rates with 12-wk regimens

– SVR12 in all 68 pts who have reached time point

SVR Rates With 12 or 24 Wks of Daclatasvir + Sofosbuvir ± RBV Very high SVR24 rates with all 24-wk

regimens across genotypes

Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

SOF + DCV + RBVSOF LI + DCV SOF + DCV SOF + DCV (12 wk)

SOF + DCV + RBV (12 wk)

93

GT2/3

8893 94

GT1

HC

V R

NA

< L

LO

Q (

%)

100

80

60

40

20

0

100

80

60

40

20

EOT* SVR4

98 95100 100

EOT* SVR24 EOT*

100 100100 100100 100 100 100

0

*EOT includes pts who discontinued early, with last visit considered EOT.


NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Pts Subjects primarily GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%)

BMI > 30: 48%; advanced liver disease: 23%; HCV RNA > 800,000 IU/mL: 62%

Wk 24Wk 24 SVR4

Osinusi A, et al. AASLD 2012. Abstract LB-4.

Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 10)

Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 25)

Sofosbuvir 400 mg + RBV 600 mg (n = 25)

Part 1 (early-stage fibrosis) SVR12

90

Part 2 (all stages of fibrosis)

56

72

EOT

90

88

96

Viral Response, %

In viral kinetic study involving 10 low-dose and 15 full-dose RBV subjects, HCV RNA decrease was rapid with median HCV RNA reduction of 4.14 log10 IU/mL by Day 7

Both regimens well tolerated and resulted in significant improvement of hepatic inflammation (P < .0001)


ZENITH: VX-222 + Telaprevir + RBV in Tx-Naive Pts With GT1a or GT1b HCV Interim analysis of triple-therapy arm of randomized phase II study with VX-222

(nonnucleoside polymerase inhibitor) and BID telaprevir[1]

– Previous report demonstrated high rate of virologic breakthrough with dual therapy (VX-222 + TVR), but 4-drug therapy (VX-222 + TVR + pegIFN/RBV) associated with SVR12 rates of 83% to 90% with no virologic breakthrough[2]

Wk 12 Wk 36

1. Jacobson IM, et al. AASLD 2012. Abstract 231. 2. Di Bisceglie A, et al. EASL 2011. Abstract 1363.

Tx-naive noncirrhotic pts with GT1a HCV

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

RBV(n = 23)

End treatment if HCV RNAundetectable at Wks 2 and 8 (n = 6)

PegIFN/RBV for 24 wks if HCV RNA detectable at Wk 2 or 8 (n = 14*)

Tx-naive noncirrhotic pts with GT1b HCV

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

RBV(n = 23)

End treatment if HCV RNAundetectable at Wks 2 and 8 (n = 5)

PegIFN/RBV for 24 wks if HCV RNA detectable at Wk 2 or 8 (n = 13*)

*3 pts in the GT1a arm and 5 pts in the GT1b arm discontinued treatment at or before Wk 12.


ZENITH: Response to VX-222 + TVR + RBV in Patients With GT1a and GT1b HCV Comparable SVR12 rates in GT 1a and 1b No SAEs; safety and tolerability better than previously observed with 4-drug regimen

(with pegIFN)

Jacobson IM, et al. AASLD 2012. Abstract 231.

Virologic Outcome, % (n/N) VX-222 + TVR + RBV in GT1b(n = 23)

VX-222 + TVR + RBV in GT 1a(n = 23)

SVR12 70 (16/23) 73 (17/23)

SVR12 with no pegIFN/RBV add on 100 (5/5) 67 (4/6)

SVR12 with pegIFN/RBV add on (48 wks) 85 (11/13) 93 (13/14)

HCV RNA < 25 IU/mL

Wk 4 (RVR) 91 (21/23) 91 (21/23)

Wk 12 (cEVR) 83 (19/23) 83 (19/23)

Wks 2 and 8 83 (19/23) 65 (15/23)

HCV RNA undetectable

Wk 4 (RVR) 91 (21/23) 57 (13/23)

Wk 12 (cEVR) 83 (19/23) 83 (19/23)

Wks 2 and 8 22 (5/23) 26 (6/23)


Randomized, open-label phase IIb trial of faldaprevir (NS3/4A protease inhibitor) with BI 207127 (nonnucleoside polymerase inhibitor)

SOUND-C2: Faldaprevir + BI 207127 ± RBV in Tx-Naive Pts With GT1 HCV

Tx-naive pts with GT1 HCV

(N = 362)

Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV

(n = 81)


(n = 80)


(n = 77)

Wk 16

Faldaprevir 120 mg QD + BI 207127 600 mg BID + RBV

(n = 78)

Faldaprevir 120 mg QD + BI 207127 600 mg TID, no RBV

(n = 46)

Stratified by HCV subgenotype and IL28B genotype

Randomization to this arm stopped early due to FDA concerns regarding lack of RBV

Wk 28 Wk 40

Zeuzem S, et al. AASLD 2012. Abstract 232.


Higher SVR in pts with GT1b HCV and in pts with IL28B genotype CC

Favorable safety/tolerability with low rate of discontinuation with BID dosing

SOUND-C2: Final Efficacy Analysis of Faldaprevir + BI 207127 ± RBV in GT1 HCV

Zeuzem S, et al. AASLD 2012. Abstract 232. Reproduced with permission.

100

80

60

40

20

0

SV

R1

2 (

%)

PP ITT

PPn/N =

48/73

47/68

40/58

54/75

18/41

BI 207127 dosingDuration (wks)

RBV

TID16 +

TID28 +

TID40+

BID28 +

TID28 ‒

59 5952

69

39

66 69 69 72

44

100

80

60

40

20

0

GT 1a GT 1b

ITTn/N =

13/34

35/47

TID16 +

TID28 +

TID40+

BID28 +

TID28 ‒

38

14/32

33/48

16/34

24/43

13/30

41/48

2/18

16/28

75

44

69

4756

43

85

11

57

100

80

60

40

20

0

Non-CC CC

ITTn/N =

34/60

14/21

TID16 +

TID28 +

TID40+

BID28 +

TID28 ‒

57

32/58

14/21

28/58

12/19

38/59

16/19

11/33

7/12

67

55

67

48

63 64

84

33

58


SOUND-C2 Subanalysis: Efficacy of Treatment in Patients With Cirrhosis Among 33 cirrhotic patients, outcomes with faldaprevir + BI 207217 + RBV

similar to noncirrhotic patients

– SVR12 rates higher in GT1b vs GT1a HCV

Higher rate of discontinuations and SAEs with TID dosing

Soriano V, et al. AASLD 2012. Abstract 84. Reproduced with permission.

BI 207127 Dosing Duration (wks)

RBV

SV

R1

2 (

%)

52

0

20

40

60

80

100

11/21

57

124/217

TID16, 28, 40

+

BID28+

TID28-

67

6/ 9

70

48/69

33

1/ 3

40

17/43

Cirrhosis No cirrhosis GT1a GT1b

SV

R1

2 (

%)

43

0

20

40

60

80

100

3/ 7

57

8/ 14

TID16, 28, 40

+

BID28+

TID28-

50

2/ 4

80

4/ 5

11 2/ 18

60

15/25

Cirrhosis No Cirrhosis

TID16, 28, 40

+

BID28+

TID28-

0/ 0

33

1/ 3

42

11/26

86

37/43

43

40/93

68

84/124

n/ N =

n/ N =

Interferon- and Ribavirin-Free Regimens


Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With GT1 HCV Interim analysis of Part 1 of AI443-014: randomized, open-label,

phase IIa study with daclatasvir (NS5A inhibitor), asunaprevir (NS3 protease inhibitor), and BMS-791325 (nonnucleoside polymerase inhibitor)

Everson GT, et al. AASLD 2012. Abstract LB-3.

Treatment-naive noncirrhotic pts with GT1 HCV

(N = 32)

Daclatasvir 60 mg QD + Asunaprevir 200 mg BID +

BMS-791325 75 mg BID(n = 16)

Daclatasvir 60 mg QD + Asunaprevir 200 mg BID +

BMS-791325 75 mg BID(n = 16)

Wk 24Stratification by HCV

subgenotype (1a vs 1b) Wk 12


Response to Daclatasvir, Asunaprevir, and BMS-791325 in Modified ITT Analysis

Both regimens generally well tolerated, with no discontinuations due to AEs

– Infrequent SAEs, grade 3/4 AEs, or grade 3/4 lab abnormalities

Everson GT, et al. AASLD 2012. Abstract LB-3. Reproduced with permission.

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

24-Wk Treatment(n = 16)

100

80

60

40

20

0Wk 4 Wk 12 EOT SVR4

100 9494

94

Missing dataHCV RNA < LLOQTD or TND

12-Wk Treatment(n = 16)

100

80

60

40

20

0Wk 4 Wk 12 EOT SVR4 SVR12

100 88 100 94 94

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

New Peginterferons


D-LITE: PegIFN lambda-1a + RBV + Daclatasvir or Asunaprevir in GT1 HCV Interim analysis of randomized, double-blind phase IIb study with pegIFN

lamba-1a (a type III IFN) plus daclatasvir (NS5A inhibitor), asunaprevir (NS3 protease inhibitor)

Vierling JM, et al. AASLD 2012. Abstract LB-9.

Tx-naive pts with GT1 HCV

(N = 119)

Daclatasvir 60 mg QD +PegIFN lambda-1a 180 µg SC QW +

RBV (n = 41)

Asunaprevir 200 mg BID +PegIFN lambda-1a 180 µg SC QW +

RBV (n = 38)

No PDR*: PegIFN lambda-1a/RBV

Stratified by HCV GT1 subgenotype, IL28B genotype

PegIFN alfa-2a 180 µg SC QW + RBV

(n = 40)

Wk 24 Wk 48

PDR: follow-up

No PDR*: PegIFN lambda-1a/RBV

PDR: follow-up

*PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12.


D-LITE: Virologic Outcomes in Patients With Protocol-Defined Response Most patients achieved PDR, qualified for shortened therapy Higher SVR12 rates in GT1b HCV, but high response rates regardless of IL28B genotype

Vierling JM, et al. AASLD 2012. Abstract LB-9.

Outcome, % PegIFN lamba-1a + RBV + Daclatasvir(n = 41)

PegIFN lamba-1a + RBV + Asunaprevir(n = 38)

PDR 90 84

PDR+ pts only (n = 37) (n = 32)

RVR 73 91

cEVR 100 100

eRVR 73 91

SVR4 78 84

SVR12 76 75

SVR12 by HCV subtype, % (n/N)

1a 65 (15*/23) 67 (14†/21)

1b 93 (13*/14) 91 (10*/11)

SVR12 by IL28B genotype, % (n/N)

Non-CC 75 (9/12) 90 (9/10)

CC 76 (19/25) 68 (15/22)

*6 IL28B CC; †5 IL28B CC.


D-LITE: Substudy in Japanese Patients With GT1 HCV In small Japanese substudy,

100% SVR4 rates in both arms In asunaprevir arm, the 1 patient

without PDR discontinued due to AE at Wk 3

Daclatasvir arm better tolerated than asunaprevir arm

– 1 SAE in asunaprevir arm

– More grade 3/4 AEs with asunaprevir (80% vs 13%)

– More grade 3/4 lab abnormalities with asunaprevir

Izumi N, et al. AASLD 2012. Abstract 234.

Virologic Response

PDR EOTR SVR4

PDR+ Only

100 100

Pat

ien

ts (

%)

0

20

40

60

80

100

8/8

5/6

8/8

5/5

8/8

5/5

100100100

83

PegIFN lambda-1a + RBV + daclatasvirPegIFN lambda-1a + RBV + asunaprevir

n/ N =

Hepatitis B Treatment


Response-Guided PegIFN-Based Therapy in HBeAg-Positive Patients Pooled analysis of 3 global randomized studies (N = 803)[1]

– Phase III study of pegIFN[2]

– HBV 99-01 study[3]

– Neptune study[4]

Response observed in

– 23% with HBeAg loss with HBV DNA < 2000 IU/mL (n = 182)

– 5% with HBsAg loss at 6 mos posttreatment (n = 39)

HBsAg levels at Wks 12 and 24 predicted response to therapy

HBV genotypic–specific stopping rules proposed

– Low response rates if HBsAg > 20,000 IU/mL at Wk 24 in all genotypes

1. Sonneveld MJ, et al. AASLD 2012. Abstract 23. 2. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.3. Janssen HL, et al. Lancet. 2005;365:123-129. 4. Liaw YF, et al. Hepatology. 2011;54:1591-1599.


HBsAg Decline During PegIFN Therapy Varies According to HBV Genotype HBsAg decline differed by HBV

genotype

Sustained HBsAg decrease seen in pts with response to pegIFN but typically not in nonresponders

Wk 24 HBsAg level predicted response at 6 mos posttreatment, regardless of genotype

Sonneveld MJ, et al. AASLD 2012. Abstract 23. Reproduced with permission.

PegIFN therapy

GT A (n = 103)

GT B (n = 205)

GT C (n = 386)

GT D (n = 110)

-2.0

-1.5

-1.0

-0.5

0.0

12 24 EOT EOFBL

Wks

HB

sAg

Dec

lin

e (l

og

IU

/mL

)

Outcome, % HBsAg Level at Wk 24, IU/mL

< 1500(n = 253)

1500-20,000

(n = 373)

> 20,000(n = 162)

P Value

HBeAg loss and HBV DNA < 2000 IU/mL

45 16 3 < .001

HBsAg loss 15 0 0 < .001

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