Highlights of AASLD 2012 clinicaloptions.com/hepatitis

Highlights of AASLD 2012

CCO Official Conference Coverage

of the 2012 Annual Meeting of the American Association for the Study of Liver Diseases November 9-13, 2012 Boston, Massachusetts In partnership with This program is supported by educational grants from This program is supported by an educational grant from

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

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Highlights of AASLD 2012 clinicaloptions.com/hepatitis

Faculty Graham R. Foster, FRCP, PhD

Professor of Hepatology

The Liver Unit

Consultant Hepatologist

Queen Marys University of London London, United Kingdom

Paul Y. Kwo, MD

Professor of Medicine Medical Director of Transplantation

Division of Medicine/Gastroenterology/Hepatology Indiana University School of Medicine Indianapolis, Indiana

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

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 C Current Therapy

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx-Naive Pts With GT1 HCV Infection

Randomized, multicenter, open-label phase III noninferiority trial

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

IL28B

GT (CC, CT, TT)

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)

Wk 12

PegIFN/RBV

Wk 24 RVR

Follow-up

No RVR

PegIFN/RBV

RVR

Follow-up

Wk 48

PegIFN/RBV

No RVR

PegIFN/RBV

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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

SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups Similar safety and tolerability profile in both treatment arms TVR q8h/PR TVR BID/PR 100

92 87 81

80

68 68 78 65 66

60

59 58

40 20 0 n/ N = 92/ 106

CC

97/ 105 141/ 208

CT

139/ 206 37/ 57

TT

38/ 58

IL28B GT

Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission. 209/ 268 213/ 264

F0-2

61/ 103 61/ 105

F3/4 Liver Disease Status

Highlights of AASLD 2012 clinicaloptions.com/hepatitis    

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) 100 80

100 72 62

Reasons for discontinuation – SAE (n = 12) – Lack of viral response (n = 11) – Pt preference (n = 6) – Loss of insurance (n = 2) 60 40 20 n/ N= 0 50/ 50 36/ 50 31/ 50

22

11/ 50

16

8/ 50 Gallegos-Orozco JF, et al. AASLD 2012. Abstract 53.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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

Wk 72 Wk 24 Wk 48

Stop therapy; 48-wk follow-up (n = 95) 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; 24-wk follow-up *47 patients dropped out and did not reach randomization at Wk 24.

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

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

100 80 24-wk pegIFN/RBV 48-wk pegIFN/RBV

73 63 61

60

52 52 54

40 20 n/N = 0

Odds Ratio 95% CI P Value

49/ 95 57/ 93

ITT (n = 188)

0.68

0.38-1.21

.1934

49/ 95 51/ 81

Per Protocol (n = 176)

0.63

0.35-1.16

.1461

49/ 90 46/ 63

Study Completer (n = 153)

0.44

0.22-0.89

.0231

 Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm Cheinquer H, et al. AASLD 2012. Abstract 156. Reproduced with permission.

Hepatitis C Current Therapy: Anemia Management

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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]

Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks from initiation of lead-in

Pts with Hb ≤10 g/dL* during BOC-based therapy (N = 500)

RBV Dose Reduction

(by 200-400 mg/day) (n = 249) †

Erythropoietin

40,000 IU/wk (n = 251) †   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 *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. 1. Poordad F, et al. AASLD 2012. Abstract 154. 2. Lawitz E, et al. AASLD 2012. Abstract 50.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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] 100

86 86

RBV dose reduction Erythropoietin 80

71 71 56 56

60 40 20 n/N = 0 178/ 249 178/ 251 111/ 129 107/ 124 67/ 120 71/ 121

All Pts Undetectable Detectable

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis   

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

SVR, % (n/N)

RBV dose reduction

Noncirrhotic (n = 438)

73 (162/221) Erythropoietin 72 (157/217)

*P

= .5966 for difference between arms among pts with cirrhosis.

Cirrhotic (n = 48)

57 (13/23)* 64 (16/25)* Lawitz E, et al. AASLD 2012. Abstract 50.

HCV/HIV-Coinfected Patients

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

Study 110: Telaprevir + PegIFN/RBV in GT1 HCV Tx-Naive HCV/HIV Coinfection

Multicenter, randomized, double-blind, placebo-controlled phase II trial

Wk 12 Wk 48 Wk 60 (SVR12) WK 72 (SVR24)

Part A: No Current ART

HCV/HIV-coinfected patients, CD4+ cell count ≥ 500 cells/mm 3 , HIV 1 RNA ≤ 100,000 copies/mL (N = 13)

TVR † 750 mg q8h

+

PegIFN/RBV Placebo

+

PegIFN/RBV PegIFN/RBV

(n = 7)

PegIFN/RBV

(n = 6)

Follow-up

Part B: Stable ART

HCV/HIV-coinfected patients on stable ART,* CD4+ cell count ≥ 300 cells/mm 3 , HIV 1 RNA ≤ 50 copies/mL (N = 47)

TVR † 750 mg q8h

+

PegIFN/RBV Placebo

+

PegIFN/RBV PegIFN/RBV

(n = 31)

PegIFN/RBV

(n = 16)

Follow-up

*Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC).

† TVR dose increased to 1125 mg q8h with EFV.

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

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

 100 Higher SVR24 rate with TVR-based therapy Telaprevir + PR Placebo + PR  No significant drug –drug interactions with TVR and ART – TVR plasma levels similar in patients with or without ART

80

80

74

60

45 71 69 50 50

– EFV and ATV/RTV plasma levels similar in patients with or without TVR 40

33

 No HIV breakthroughs in patients using ART during HCV treatment 20 n/N = 0 28/ 38 10/ 22 5/ 7 2/ 6 11/ 16 4/ 8 12/ 15 4/ 8  Safety and tolerability similar to treatment in patients with HCV monoinfection Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission.

Novel DAAs + PegIFN/RBV

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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)

Wk 12 Wk 24

SOF

+

PegIFN/RBV

(n = 52) Treatment naive, noncirrhotic patients* (N = 332)

SOF

+

SOF

+

PegIFN/RBV

(n = 125)

PegIFN/RBV

(n = 155)

SOF

(n = 75)

SOF

+

RBV

(n = 75) *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. Hassanein T, et al. AASLD 2012. Abstract 230.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis   

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   100 80 60 40 20 0

98 99 99 90 92 91

SOF + PR 12 wks SOF + PR 24 wks SOF + PR 12 + 12 wks

EOT SVR12

11 patients (1 in 12-wk group) who attained SVR12 subsequently lost to follow-up No relapse after SVR12 in any group 100 80 60 40 20 0

100 100 82 100

GT4 HCV (n = 11) GT6 HCV (n = 5)  

EOT SVR12

11/11 patients with genotype 4 HCV achieved RVR and EOT response – 2 LTFU without posttreatment data No relapse after SVR12 in either group Hassanein T, et al. AASLD 2012. Abstract 230.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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) Treatment naive (n = 25) Null responders (n = 10)

SOF

+

RBV SOF

+

RBV

Wk 12

EOT Patients, % SVR4 SVR12 100 88 84 100 10 10

Treatment naive (n = 25) Null responders (n = 9)

SOF

+

GS-5885

+

RBV SOF

+

GS-5885

+

RBV 100 100 100 100*

 No SAEs related to study drugs; AE profile consistent with RBV toxicity profile *Data reported for 3 pts only. Data collection ongoing. Gane EJ, et al. AASLD 2012. Abstract 229.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

ELECTRON: Sofosbuvir in Patients With GT2/3 HCV

Interim analysis of nonrandomized phase II study with SOF (nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor)

Wk 4 Wk 8 Wk 12

SVR, %

Treatment-naive, GT2/3 HCV (N = 95) (n = 10)

SOF + PegIFN + RBV

(n = 10)

SOF + PegIFN + RBV

(n = 9)

SOF + PegIFN + RBV

(n = 11) (n = 10) (n = 10) (n = 25) (n = 10)

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

Treatment experienced, GT2/3 HCV (n = 25)

SOF + RBV

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

100 (SVR24) 100 (SVR24) 100 (SVR24) 100 (SVR24) 60 (SVR8) 60 (SVR24) 64 (SVR12) 100 (SVR24) 68 (SVR12)

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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

Wk 24 Wk 48

Noncirrhotic pts with GT1 HCV and previous partial response to pegIFN/RBV (N = 151)

Danoprevir/RTV

+

Mericitabine

+

RBV*

(n = 52)

Danoprevir/RTV

+

PegIFN/RBV

(n = 49)

Danoprevir/RTV

+

Mericitabine

+

PegIFN/RBV

(n = 50) Noncirrhotic pts with GT1 HCV and previous null response to pegIFN/RBV (N = 228)

Danoprevir/RTV

+

Mericitabine

+

RBV*

(n = 77)

Danoprevir/RTV

+

Mericitabine + PegIFN/RBV

(n = 77)

Danoprevir/RTV

+

Mericitabine + PegIFN/RBV

(n = 74)

PegIFN/RBV

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

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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

Response rates highest with 4-drug therapy and lowest with pegIFN-free therapy in both cohorts DNV/RTV + MCB + RBV DNV/RTV + pegIFN/RBV DNV/RTV + MCB + pegIFN/RBV   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 100 80 60 40 20 n/N = 0

Prior Partial Response 87 94 94 86

20/ 23 46/ 49 47/ 50

EOT 39 56

9/ 23 27/ 48 43/ 50

SVR12 Prior Null Response 88 96 84

28/ 32 73/ 76

EOT 55

17/ 31 62/ 74

SVR12

100 80 60 40 20 n/N = 0

91 GT1b 96 100

19/ 21 25/ 26 30/ 30

30

8/ 27

GT1a 75

18/ 24

73

32/ 44 Feld JJ, et al. AASLD 2012. Abstract 81. Reproduced with permission.

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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)

Wk 24

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

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

Outcomes With Daclatasvir + Asunaprevir ± PegIFN or RBV in Null Responders

  High response rates with 4-drug regimen of DCV + ASV + pegIFN/RBV  100 80 Lower response rates with 2-drug regimen (all GT1b pts) – Better response with ASV 200 mg BID vs ASV 200 mg QD

100 100 90 95 89

DCV + ASV (BID) + PR DCV + ASV (QD) + PR DCV + ASV (BID) DCV + ASV (QD)

78 70 65

60 40    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 20 n/N = 0 20/ 20 21/ 21

EOT

18/ 20 20/ 21

SVR24

16/ 18 14/ 20

EOT

14/ 18 13/ 20

SVR12

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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 Placebo + PR Simeprevir 150 mg QD + PR

SVR24 by METAVIR Score SVR24 by Prior IFN Response in

100 80 60

71 79 56 62

100 80 60

65

40 40

4

20 n/N = 0 5/ 7 15/ 19 1/ 23 38/ 68 0/ 10 24/ 39 20 n/N = 0 0/ 10 17/ 26

PILLAR Naive, F3 ASPIRE Tx Exp’d, F3 + F4 ASPIRE Tx Exp’d, F4 Only Relapser

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

Pts With F3/F4 10 67

1/ 10 14/ 21

Partial Responder 33

0/ 3 7/ 21

Null Responder

Novel DAAs + Ribavirin Interferon-Free Regimens

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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 8 Wk 12 Wk 24

Cohort 1: Treatment-naive GT1 HCV pts (N = 438)

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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 12 Wk 24

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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 100 80 60 40 20 0

86 84 96 96 Treatment-Naive Patients 79 100 82 100 100 88 100 85 88 100 96 83

n = 56 24 1a 1b ABT-450 ABT-267 ABT-333 RBV 8

wks

29 12 1a 1b ABT-450 ABT-333 RBV 52 27 1a 1b ABT-450 ABT-267 RBV 12 52 25 1a 1b ABT-450 ABT-267 ABT-333

wks 98 100 96 100

54 25 1a 1b ABT-450 ABT-267 ABT-333 RBV

Null Responders 100 81 100 81 89 100 100 89

26 18 1a 1b 28 17 1a 1b ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV 12

wks

Kowdley KV, et al. AASLD 2012. Abstract LB-1. Reproduced with permission. Observed data (above bar) ITT (within bar)

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

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

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

Wk 1 Wk 12 Wk 24

Treatment-naive noncirrhotic patients with GT1 HCV (N = 126) Treatment-naive noncirrhotic patients with GT2/3 HCV (N = 44)

SOF SOF

+

DCV

(n = 15)

SOF

+

DCV

(n = 14)

SOF

+

DCV

+

RBV

(n = 15)

SOF

+

DCV

(n = 41)

SOF

+

DCV

+

RBV

(n = 41)

SOF SOF

+

DCV

(n = 16)

SOF

+

DCV

(n = 14)

SOF

+

DCV

+

RBV

(n = 14) Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

SVR Rates With 12 or 24 Wks of Daclatasvir + Sofosbuvir ± RBV

 Very high SVR24 rates with all 24-wk regimens across genotypes 100

GT1 100 100 100 93 100 100 GT2/3 94 100 100



88 100 93

Similar high SVR4 rates with 12-wk regimens – SVR12 in all 68 pts who have reached time point 100

100 100 98 95

80 80 60 40 20 0

EOT* SVR24 EOT* SVR24

SOF LI + DCV SOF + DCV + RBV SOF + DCV *EOT includes pts who discontinued early, with last visit considered EOT.

Sulkowski MS, et al. AASLD 2012. Abstract LB-2. 60 40 20 0

EOT* SVR4

SOF + DCV (12 wk) SOF + DCV + RBV (12 wk)

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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%

Part 1 (early-stage fibrosis)

Wk 24

EOT Viral Response, % SVR4 SVR12 90 Sofosbuvir 400 mg

+

RBV 1000/1200 mg

(n = 10)

90 Part 2 (all stages of fibrosis) Sofosbuvir 400 mg

+

RBV 600 mg

(n = 25)

88 56 Sofosbuvir 400 mg

+

RBV 1000/1200 mg

(n = 25)

96 72

  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 log 10 IU/mL by Day 7 Both regimens well tolerated and resulted in significant improvement of hepatic inflammation (

P

< .0001) Osinusi A, et al. AASLD 2012. Abstract LB-4.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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

Tx-naive noncirrhotic pts with GT1a HCV

VX-222

400 mg BID +

Telaprevir

1125 mg BID +

RBV

(n = 23)

End treatment

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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)

Virologic Outcome, % (n/N)

SVR12  SVR12 with no pegIFN/RBV add on  SVR12 with pegIFN/RBV add on (48 wks) HCV RNA < 25 IU/mL  Wk 4 (RVR)  Wk 12 (cEVR)  Wks 2 and 8 HCV RNA undetectable  Wk 4 (RVR)  Wk 12 (cEVR)  Wks 2 and 8

VX-222 + TVR + RBV in GT1b (n = 23)

70 (16/23) 100 (5/5) 85 (11/13) 91 (21/23) 83 (19/23) 83 (19/23) 91 (21/23) 83 (19/23) 22 (5/23)

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

73 (17/23) 67 (4/6) 93 (13/14) 91 (21/23) 83 (19/23) 65 (15/23) 57 (13/23) 83 (19/23) 26 (6/23) Jacobson IM, et al. AASLD 2012. Abstract 231.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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

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

Stratified by HCV subgenotype and IL28B genotype

Tx-naive pts with GT1 HCV (N = 362)

Wk 16

Faldaprevir

120 mg QD +

BI 207127

600 mg TID +

RBV

(n = 81)

Faldaprevir

120 mg QD +

BI 207127

600 mg TID +

RBV

(n = 80)

Faldaprevir

120 mg QD +

BI 207127

600 mg TID +

RBV

(n = 77)

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)

Wk 28 Wk 40

Randomization to this arm stopped early due to FDA concerns regarding lack of RBV Zeuzem S, et al. AASLD 2012. Abstract 232.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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

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 100 80 60 40

66

59 20 0 PP n/N = 48/ 73

BI 207127 dosing Duration (wks) RBV

TID 16 +

69

59 47/ 68 TID 28 + PP

69

52 ITT

72

69

44

39 40/ 58 TID 40 + 54/ 75 BID 28 + 18/ 41 TID 28 ‒ GT 1a GT 1b 100 80

75 85 69

60 40

38 44 47 56 43 57

20

11

0 ITT n/N = 13/ 34 35/ 47 14/ 32 33/ 48 16/ 34 24/ 43 13/ 30 41/ 48 2/ 18 16/ 28 TID 16 + TID 28 + TID 40 + BID 28 + TID 28 ‒ Non-CC CC 100 80 60

57 67 55 67 48 63 64 84

40

33 58

20 0 ITT n/N = 34/ 60 14/ 21 32/ 58 14/ 21 28/ 58 12/ 19 38/ 59 16/ 19 11/ 33 7/ 12 TID 16 + TID 28 + TID 40 + BID 28 + TID 28 ‒ Zeuzem S, et al. AASLD 2012. Abstract 232. Reproduced with permission.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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 100 80 60 40 20 0

52

Cirrhosis

57

n/ N = 11/ 21 124/ 217

BI 207127 Dosing Duration (wks) RBV

TID 16, 28, 40 +

67

6/ 9 No cirrhosis

70

48/ 69 BID 28 +

33

1/ 3 TID 28 -

40

17/ 43 GT1a GT1b 100 80 60 40 20 0

86 80 68 43 57 50 33

n/ N = 3/ 7 8/ 14 2/ 4 4/ 5

Cirrhosis

TID 16, 28, 40 + BID 28 + 0/ 0 1/ 3 TID 28 -

43

40/ 93 84/ 124

No Cirrhosis

TID 16, 28, 40 + BID 28 + -

60 42

11/ 26 37/ 43

11

2/ 18 15/ 25 TID 28 Soriano V, et al. AASLD 2012. Abstract 84. Reproduced with permission.

Interferon- and Ribavirin-Free Regimens

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

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)

Stratification by HCV subgenotype (1a vs 1b)

Wk 12 Wk 24

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis

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

100 HCV RNA < LLOQ TD or TND

100 24-Wk Treatment

(n = 16)

94 94 94

100 Missing data

100 12-Wk Treatment

(n = 16)

88 100 94 94

80 80 60 40 60 40 20 20  0 0

Wk 4 Wk 12 EOT SVR4 Wk 4 Wk 12 EOT SVR4 SVR12

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.

New Peginterferons

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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)

Wk 24 Wk 48

Stratified by HCV GT1 subgenotype,

IL28B

genotype

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)

PDR

: follow-up

No PDR*: PegIFN lambda-1a/RBV PDR

: follow-up

No PDR*: PegIFN lambda-1a/RBV PegIFN alfa-2a

180 µg SC QW +

RBV

(n = 40) *PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12.

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

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

Outcome, %

PDR PDR+ pts only  RVR   cEVR eRVR   SVR4 SVR12 SVR12 by HCV subtype, % (n/N)  1a  1b SVR12 by

IL28B

genotype, % (n/N)   Non-CC CC

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

90 (n = 37) 73 100 73 78 76 65 (15*/23) 93 (13*/14) 75 (9/12) 76 (19/25)

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

84 (n = 32) 91 100 91 84 75 67 (14 † /21) 91 (10*/11) 90 (9/10) 68 (15/22) *6

IL28B

CC; † 5

IL28B

CC.

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

Highlights of AASLD 2012 clinicaloptions.com/hepatitis 

D-LITE: Substudy in Japanese Patients With GT1 HCV

In small Japanese substudy , 100% SVR4 rates in both arms PegIFN lambda-1a + RBV + daclatasvir PegIFN lambda-1a + RBV + asunaprevir  In asunaprevir arm, the 1 patient without PDR discontinued due to AE at Wk 3

Virologic Response

 Daclatasvir arm better tolerated than asunaprevir arm

100 100 100

100

100 100

– 1 SAE in asunaprevir arm

83

80 60 – More grade 3/4 AEs with asunaprevir (80% vs 13%) 40 20 0 n/ N = 8/ 8

PDR

5/ 6 8/ 8 5/ 5 EOTR 8/ 8 5/ 5 SVR4 – More grade 3/4 lab abnormalities with asunaprevir

PDR+ Only

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

Hepatitis B Treatment

Highlights of AASLD 2012 clinicaloptions.com/hepatitis    

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.

Highlights of AASLD 2012 clinicaloptions.com/hepatitis  

HBsAg Decline During PegIFN Therapy Varies According to HBV Genotype

HBsAg decline differed by HBV genotype  Wk 24 HBsAg level predicted response at 6 mos posttreatment, regardless of genotype Sustained HBsAg decrease seen in pts with response to pegIFN but typically not in nonresponders 0.0

-0.5

GT D

(n = 110)

Outcome, % HBsAg Level at Wk 24, IU/mL < 1500

(n = 253)

1500 20,000

(n = 373)

> 20,000

(n = 162)

P

Value

-1.0

-1.5

GT C

(n = 386)

GT A

(n = 103)

GT B

(n = 205) HBeAg loss and HBV DNA < 2000 IU/mL HBsAg loss 45 15

PegIFN therapy

-2.0

BL 12 24 EOT EOF

Wks

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

16 0 3 0 < .001

< .001

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