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clinicaloptions.com/hepatitis HCV Investigational Agents April 22-26, 2015 Vienna, Austria Highlights From EASL: HCV Investigational Agents CCO Independent Conference Coverage of the 2015 Annual Meeting of the European Association for the Study of the Liver* *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 AbbVie, Gilead Sciences, and Merck.
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Page 1: EASL 2015. HCV Investigational Agents

clinicaloptions.com/hepatitisHCV Investigational Agents

April 22-26, 2015Vienna, Austria

Highlights From EASL: HCV Investigational AgentsCCO Independent Conference Coverage of the 2015 Annual Meeting of the European Association for the Study of the Liver*

*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 fromAbbVie, Gilead Sciences, and Merck.

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About These Slides

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These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])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

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Faculty

Andrew J. Muir, MDChief, Division of GastroenterologyAssociate Professor of MedicineDepartment of MedicineDirector, Gastroenterology/ Hepatology ResearchDuke Clinical Research InstituteDuke University School of MedicineDurham, North Carolina

David R. Nelson, MD Professor of Medicine Assistant Vice President for Research University of FloridaGainesville, Florida

Norah Terrault, MD, MPH Professor of Medicine and Surgery

Director, Viral Hepatitis CenterDivision of GastroenterologyUniversity of California, San FranciscoSan Francisco, California

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Disclosures

Andrew J. Muir, MD, has disclosed that he has received funds for research support from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hologic, Intercept, Janssen, Merck, NGM Biopharm, and Roche and has received consulting fees from AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, Lumena, Merck, Regulus Therapeutics, Salix, and Theravance.

David R. Nelson, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.

Norah Terrault, MD, MPH, has disclosed that she has received funds for research support from AbbVie, Biotest, Esai, Gilead Sciences, Novartis, and Vertex and has received consulting fees from Achillion, Biotest, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.

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Summary of Direct-Acting Antivirals Discussed in This SlidesetDrug Class Dosing

Daclatasvir NS5A inhibitor 60 mg QD

Elbasvir NS5A inhibitor 50 mg QD*

Grazoprevir NS3/4A protease inhibitor 100 mg QD*

GS-5816 NS5A inhibitor 100 mg QD‡

GS-9451 NS3/4A protease inhibitor 80 mg QD

GS-9857 NS3/4A protease inhibitor 100 mg QD

GS-9669 NS5B nonnucleoside polymerase inhibitor 500 mg QD

Ledipasvir NS5A inhibitor 90 mg QD†

Sofosbuvir NS5B nucleotide polymerase inhibitor 400 mg QD†‡

*Grazoprevir and elbasvir may be coformulated.†Ledipasvir and sofosbuvir may be coformulated.‡Sofosbuvir and GS-5816 may be coformulated.

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Phase II/III Studies of Grazoprevir/Elbasvir

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Grazoprevir/Elbasvir Studies: Overview

Study Name Description

C-EDGE TN12 wks of grazoprevir/elbasvir in treatment-naive pts with

GT1, 4, or 6 HCV infection

C-EDGE TE12 or 16 wks of grazoprevir/elbasvir ± RBV in pts with GT1, 4, or 6 HCV and

previous failure of pegIFN/RBV

C-EDGE Coinfection12 wks of grazoprevir/elbasvir in HCV treatment-naive pts coinfected with HIV

and GT1, 4, or 6 HCV

C-SALVAGE12 wks of grazoprevir/elbasvir + RBV in pts with GT1 HCV and previous failure

of HCV PI + pegIFN/RBV

C-SCAPE12 wks of grazoprevir ± elbasvir ± RBV in treatment-naive, noncirrhotic pts with

GT2, 4, 5, or 6 HCV

C-WORTHY C8 wks of grazoprevir/elbasvir ± RBV in treatment-naive, noncirrhotic pts with

GT1b HCV

C-SWIFTShort-duration therapy with grazoprevir/elbasvir + sofosbuvir in treatment-

naive, GT1 or 3 HCV–infected pts ± cirrhosis

C-SURFER12 wks of grazoprevir/elbasvir in pts with GT1 HCV infection

and stage 4 or 5 CKD

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C-EDGE TN: 12-Wk Grazoprevir/Elbasvir for Treatment-Naive Pts With GT1/4/6 HCV International, randomized, blinded, placebo-controlled, parallel-group phase III

trial

Pts well matched at baseline: 91% infected with GT1a or 1b HCV, 68% HCV RNA > 800,000 IU/mL, 22% cirrhotic

Fewer white pts in immediate vs deferred treatment arm (60% vs 70%, respectively)

Grazoprevir/Elbasvir(n = 316)

Placebo(n = 105) Grazoprevir/Elbasvir

Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily.

Treatment-naiveGT1, 4, or 6

HCV–infected pts

(N = 421)

Open-label period

TreatmentWk 12

Follow-upWk 4

Follow-upWk 16

Zeuzem Z, et al. EASL 2015. Abstract G07.

Randomized period

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C-EDGE TN: Efficacy Results

Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission.

Subgroup analysis: significantly lower SVR12 rates in pts with baseline HCV RNA > 800,000 IU/mL

‒ No differences according to race, IL28B status, presence of cirrhosis Lower SVR12 rates in pts having baseline NS5A RAVs associated with > 5-fold loss of

susceptibility to elbasvir

SV

R12

(%

)

All Pts GT1a GT1b GT4 GT6

95 92 99 10080

299/316

144/157

129/131

18/18

8/10n/N =

SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype

100

80

60

40

20

0

Non-virologic failure 4 3 1 0 0

Breakthrough 1 1 0 0 0

Relapse 12 9 1 0 2

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C-EDGE TN: Adverse Events

Grazoprevir/elbasvir generally well tolerated in cirrhotic, noncirrhotic pts

– No serious treatment-related AEs

– 1% discontinued active drugs for AEs

Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission.

Adverse Events, %

Noncirrhotic Pts Cirrhotic Pts

GZR/EBV(n = 246)

Pbo(n = 83)

GZR/EBV(n = 70)

Pbo(n = 22)

≥ 1 AE 71 69 54 68

Drug-related AE

39 39 26 41

SAE 3 4 3 0

Drug-related SAE

0 0 0 0

Discontinued for AE

1 0 1 5

Death < 1 0 1 0

Parameter, % GZR/EBV(n = 316)

Pbo (n = 105)

Common AEs (> 5%) Headache 17 18 Fatigue 16 17 Nausea 9 8 Arthralgia 6 6

Late ALT or AST elevation > 2 to 5 x ULN 1.0 3.8 > 5 x ULN 1.3 0

Total bilirubin elevation > 2 to 5 x baseline 0.9 0 > 5 x baseline 0.3 0

Decreased hemoglobin Grade 1/2 2.9 3.8 Grade 3/4 0 0

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C-EDGE TE: Grazoprevir/Elbasvir ± RBV for Treatment-Experienced Pts International, randomized, open-label, parallel-group, phase III trial

Pts well matched at baseline: ~ 90% infected with GT1a or 1b HCV, ~ 35% cirrhotic

Fewer GT4 HCV–infected pts in 16-wk arms, no GT6 HCV–infected pts in 12-wk arms

Grazoprevir/Elbasvir(n = 105)

Grazoprevir/Elbasvir + RBV(n = 104)

PegIFN/RBV-experienced pts

with GT1, 4, or 6 HCVinfection (N = 420)

Grazoprevir/Elbasvir(n = 105)

Wk 12

Grazoprevir/Elbasvir + RBV(n = 106)

Wk 16

Kwo P, et al. EASL 2015. Abstract P0886.

Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily; weight-based RBV

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0

100

80

60

40

20

C-EDGE TE: Efficacy Results

Subgroup analysis: 99% SVR12 in black pts and no evidence of reduced efficacy at high baseline HCV RNA (cutoff = 2 million IU/mL)

Among pts with GT1a HCV infection, previous response and cirrhosis status did not impact SVR12 rates

SVR12 rate reduced (52.4%) in GT1a HCV–infected pts with baseline NS5A variants associated with > 5-fold change in elbasvir susceptibility

Kwo P, et al. EASL 2015. Abstract P0886. Reproduced with permission.

GZR/EBV GZR/EBV + RBV GZR/EBV + RBV GZR/EBV

92

97/105

98/104

97/105

103/106

94 9792

SV

R12

(%

)12 Wks 16 Wks

n/N =

Breakthrough 0 0 1 0

Rebound 0 0 2 0

Relapse 6 6 4 0

LTFU/Early DC 2 0 1 3

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C-EDGE TE: Adverse Events

Kwo P, et al. EASL 2015. Abstract P0886. Reproduced with permission.

AEs, %12 Wks ofGZR/EBV (n = 105)

12 Wks ofGZR/EBV + RBV

(n = 104)

16 Wks ofGZR/EBV (n = 105)

16 Wks ofGZR/EBV + RBV

(n = 106)

Serious AE 3.8 2.9 2.9 3.8

Death 0 0 0 0

Discontinued due to AE 1.0 1.0 0 4.6

Hemoglobin < 10 g/dL 0 8.7 0 20.8

Total bilirubin > 5 x baseline 0 0 0 0

Late ALT or AST elevation > 5 x ULN 0 1 4 0

Common AEs*

Fatigue 19.0 26.9 16.2 30.2

Headache 21.0 20.2 19.0 18.9

Nausea 8.6 14.4 3.8 17.0

*Occurring in > 10% of pts.

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C-EDGE Coinfection: Grazoprevir/Elbasvir for Pts Coinfected With HCV/HIV Multicenter, single-arm, open-label phase III trial

66% with GT1a HCV, 60% had HCV RNA > 800,000 IU/mL, 16% cirrhotic

Grazoprevir/Elbasvir(n = 218)

HCV treatment-naive pts coinfected with HIV and

GT1, 4, or 6 HCV(N = 218)

Wk 12

Rockstroh JK, et al. EASL 2015. Abstract P0887. Reproduced with permission.

Coformulated grazoprevir/elbasvir dosed orally 100/50 mg once daily

Baseline ART

Undetectable HIV-1 RNA on ART (%) 96.8

Abacavir containing 21.6

Tenofovir DF containing 75.2

Raltegravir 51.8

Dolutegravir 27.1

Rilpivirine 17.4

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0

100

80

60

20

C-EDGE Coinfection: Key Findings

No subgroup provided an efficacy advantage or disadvantage

New NS3, NS5A RAVs detected at failure in 5 of 6 pts who relapsed

Short-lived HIV-1 RNA increases occurred in 2 pts on ART during grazoprevir/elbasvir treatment: both resuppressed HIV-1 RNA without change of ART

During 12 wks of treatment, no significant changes in CD4+ cell count (n = 207)

Grazoprevir/elbasvir well tolerated: no pt discontinued for AEs and no serious treatment-related AEs

Rockstroh JK, et al. EASL 2015. Abstract P0887. Reproduced with permission.

SV

R1

2 (

%)

136/144

42/44

27/28

All Pts GT1a GT1b GT4

95.0 94.4 95.5 96.4

207/218

SVR12 With 12 Wks GZR/EBV According to Genotype

LTFU or DC* 4 3 1 0

Breakthrough 0 0 0 0

Relapse 6 4 1 1

Reinfection 1 1 0 0

*Unrelated to virologic failure.

n/N =

40

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C-SALVAGE: Grazoprevir/Elbasvir + RBV After DAA Failure in Pts With GT1 HCV International, open-label, single-arm phase II study

Forns X, et al. EASL 2015. Abstract O001. Reproduced with permission.

Grazoprevir/elbasvir orally dosed 100 mg/50 mg once daily, weight-based RBV.

Grazoprevir/Elbasvir + RBV(n = 79)

Pts with GT1 HCV and previous PI +

pegIFN/RBV therapy(N = 79)

Wk 12

Baseline Characteristic, %All Pts(N = 79)

Evaluable Pts*Baseline NS3 RAVs

(n = 34)No Baseline NS3 RAVs

(n = 44)HCV genotype 1a 38.0 67.6 15.9 1b 62.0 32.4 84.1

Cirrhosis 43.0 44.1 43.2Previous PI Boceprevir 35.4 29.4 38.6 Telaprevir 54.4 55.9 54.5 Simeprevir 10.1 14.7 6.8

Previous virologic failure 83.5 94.1 75.0*1 pt did not have baseline NS3 sequencing data available.

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100

60

40

20

0

80

C-SALVAGE: Efficacy Results

Forns X, et al. EASL 2015. Abstract O001. Reproduced with permission.

Previous TherapyPrevious All-

Cause Treatment Failures, N

Baseline RAVs, % SVR12 in Pts With Baseline RAVs, %

NS3 NS5A

Boceprevir 28 37.0 10.7 90.9*

Telaprevir 43 44.2 10.7 90.0*

Simeprevir 8 62.5 0 100

All pts 79 43.6 10.1 91.7*2 boceprevir-treated pts and 4 telaprevir-treated pts harbored quasispecies at baseline with mutations in both the NS3 and NS5A genes.

SV

R12

(%

)

76/79

Prior Non-virologic

Failure

AllPts

Prior Virologic

Failure

10096.2 95.5

63/66

13/13n/N =

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C-SALVAGE: Adverse Events

Forns X, et al. EASL 2015. Abstract O001. Reproduced with permission.

Adverse Events,* %All Pts(N = 79)

Any event relating to study drug 57.0

Occurring in ≥ 10% of pts regardless of causality

Fatigue 27.8

Headache 19.0

Asthenia 15.2

Nausea 11.7

Serious adverse events† 5.1

Discontinuation due to toxicity† 1.3

Death 0

Grade 3/4 Laboratory Abnormalities, %

All Pts(N = 79)

Grade 3 Grade 4

Total bilirubin 5.1 1.3

Direct bilirubin 2.5 0

AST/ALT 0 0

Lipase 5.1 0

Prothrombin time 0 1.3

Hemoglobin 2.5 0

Leukopenia 0 1.3

Thrombocytopenia 1.3 0

*Occurring up to 2 wks after treatment end.†None attributed to study drug.

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C-SCAPE: Grazoprevir ± Elbasvir ± RBV for Pts With GT2/4/5/6 HCV Open-label, randomized, phase II trial

In the GT4/5/6 group, 53% of pts were infected with GT4 HCV

Efficacy reduced in pts infected with GT2 HCV with baseline HCV RNA > 2 million IU/mL

Grazoprevir/elbasvir active in GT5 and 6 HCV, although pt numbers were small

GT2 (n = 56*)

Grazoprevir/Elbasvir + RBV(n = 30)

Grazoprevir + RBV(n = 26)

Grazoprevir/Elbasvir + RBV(n = 18)

Wk 12

Grazoprevir/Elbasvir (n = 18)

GT4 (n = 20)GT5 (n = 8*)GT6 (n = 8*)

Treatment-naive, noncirrhotic, HCV-

infected pts(N = 98)

*mITT population: 6 pts were excluded due to improper genotyping. Grazoprevir dosed 100 mg orally once daily; elbasvir dosed 50 mg orally once daily; RBV dosed at 800-1400 mg/day based on weight.

Brown A, et al. EASL 2015. Abstract P0771.

SVR12, %

80

73

GT4/5/6100/100/75

GT4/5/690/25/75

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C-WORTHY C: 8-Wk Grazoprevir/Elbasvir ± RBV for GT1b HCV Randomized, open-label, phase II trial

Higher HCV RNA levels for grazoprevir/elbasvir without vs with RBV at baseline

All pts who did not achieve SVR12 relapsed (n = 4); 1 pt had an NS5A RAV at baseline and failure

1 SAE in grazoprevir/elbasvir + RBV group; considered unrelated to treatment

No discontinuations due to AEs or deaths

Vierling J, et al. EASL 2015. Abstract P0769.

Grazoprevir/Elbasvir + RBV(n = 30)

Grazoprevir/Elbasvir (n = 31)

Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily.

Treatment-naive, noncirrhotic

GT1b HCV–infected pts

(N = 61)

Wk 8

SVR12, %

93

94

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C-SWIFT: Short-Duration GZR/EBV + SOF in GT1 or 3 HCV Infection

Treatment-naive noncirrhotic pts with GT1 HCV

(n = 61)

Grazoprevir/Elbasvir + SOF(n = 31)

Grazoprevir/Elbasvir + SOF(n = 30)

Grazoprevir/Elbasvir + SOF(n = 21)

Wk 4 Wk 6 Wk 8

Treatment-naive cirrhotic pts with

GT1 HCV(n = 41)

Grazoprevir/Elbasvir + SOF(n = 20)

Grazoprevir/Elbasvir + SOF(n = 15)

Treatment-naive noncirrhotic pts with GT3 HCV

(n = 29)

Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily; sofosbuvir 400 mg orally once daily.

Grazoprevir/Elbasvir + SOF(n = 14)

Treatment-naive cirrhotic pts with

GT3 HCV(n = 12)

Grazoprevir/Elbasvir + SOF(n = 12)

Wk 12

Poordad F, et al. EASL 2015. Abstract O006.

Open-label phase II trial

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C-SWIFT: GZR/EBV + SOF Efficacy Results

Pts well matched at baseline: population primarily white (93% to 100%); of pts with GT1 HCV infection, 76% to 84% had GT1a HCV; IL28B non-CC varied between arms (21% to 50%)

All pts who failed treatment relapsed; among GT1 HCV relapses, 30% developed NS5A RAVs at failure (most in 4-wk treatment group)

Higher baseline HCV RNA (> 2 million IU/mL) and presence of cirrhosis resulted in lower SVR12 rates for pts with GT3 HCV

Poordad F, et al. EASL 2015. Abstract O006. Reproduced with permission.

SV

R12

(%

)

100

80

60

40

20

04 Wks 6 Wks 6 Wks 8 Wks 8 Wks 12 Wks 12 Wks

Genotype 1 Genotype 3

33

26/30

16/20

17/18

14/15

14/14

10/11*

87 8094 93 100 91

10/30*

*Excluded pts who discontinued due to reasons other than virologic failure.

NoncirrhoticCirrhotic

n/N =

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C-SWIFT: GZR/EBV + SOF Adverse Events

Poordad F, et al. EASL 2015. Abstract O006. Reproduced with permission.

Parameter, n (%)

All Pts(N = 143)

Genotype 1 HCV Infection Genotype 3 HCV Infection

Noncirrhotic4 and 6 Wks

(n = 61)

Cirrhotic6 and 8 Wks

(n = 41)

Noncirrhotic8 and 12 Wks

(n = 29)

Cirrhotic12 Wks (n = 12)

Most common AEs

Headache 4 (3) 1 (2) 3 (7) 1 (3) 1 (8) Fatigue 2 (1) 2 (3) 0 0 1 (8) Nausea 2 (1) 2 (3) 1 (2) 1 (3) 1 (8)

Serious AEs 2 (1) 0 2*† (5) 0 0

Discontinuations due to AE 1 (1) 0 1† (2) 0 0

Deaths 0 0 0 0 0

Hemoglobin < 10 g/dL 0 0 0 0 0

Total bilirubin > 5 x baseline 0 0 0 0 0

ALT/AST > 5 x ULN 0 0 0 0 0

*Pyelonephritis (n = 1).†B-cell lymphoma (n = 1). Study drug discontinued after treatment Wk 4.

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C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4 or 5 CKD Multicenter, part-randomized, parallel-group, placebo-controlled, phase III trial

Treatment arms well matched at baseline

– Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated cirrhosis

– 75% and 77% were on hemodialysis; 32% to 36% were diabetic

– 81% and 82% were CKD stage 5 (eGFR < 15 mL/min/1.73 m2, or on hemodialysis); 18% and 19% were CKD stage 4 (eGFR 15-29 mL/min/1.73 m2)

Roth D, et al. EASL 2015. Abstract LP02.

Grazoprevir/Elbasvir(n = 111)

Placebo(n = 113)

GT1 HCV-infected pts with

stage 4/5 CKD(n = 224) Grazoprevir/Elbasvir

(n = 113)

Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group.

TreatmentWk 12

Follow-upWk 4

Follow-upWk 16

Open-label period

Randomized period

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20

Modified FullAnalysis Set

Full Analysis Set

n/N =

C-SURFER: Efficacy Results

Roth D, et al. EASL 2015. Abstract LP02. Reproduced with permission.

GZR/EBR 12 wks

Modified analysis set: pts in pharmacokinetic substudy and pts randomized to immediate treatment who received ≥ 1 drug dose; excludes pts who died or discontinued where cause not related to study treatment.Full analysis set: all pts receiving ≥ 1 drug dose.*1 pt relapsed on each arm. †6 pts in the full analysis set discontinued unrelated to treatment: lost to follow-up (n = 2), n = 1 each for death, noncompliance, withdrawal by subject, and withdrawal by physician (owing to violent behavior).

SV

R12

(%

)

9499

115/116*

115/122*†

100

6/6

100

61/61

98.2

54/55

98.9

86/87

97.6

40/41

Cirrhotic GT 1a HCV

GT 1b HCV

DiabeticOn hemodialysis

100

80

60

40

0

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C-SURFER: Adverse Events

Roth D, et al. EASL 2015. Abstract LP02. Reproduced with permission.

AE, % Grazoprevir/Elbasvir (Randomized Treatment)(n = 111)

Placebo (n = 113)

Serious AEs 14.4 16.8Discontinuation due to AE 0 4.4Death 0.9 2.7Common AEs* 75.7 84.1 Headache 17.1 16.8 Nausea 15.3 15.9 Fatigue 9.9 15.0 Insomnia 6.3 10.6 Dizziness 5.4 15.9 Diarrhea 5.4 13.3

Hb grade decrease from baseline 1 grade 24.3 26.5 2 grades 12.6 7.1 3 grades 3.6 1.8 4 grades 0 0.9

*Reported  in ≥ 10% of pts in either arm.

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Treatment Simplification Strategies

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SYNERGY: 4-6 Wks of LDF/SOF + GS-9451 ± GS-9669 in GT1 HCV Single-center, open-label, phase IIa trial

At baseline, > 60% GT1a HCV; 76% to 80% black pts, except 6-wk treatment-experienced arm, which had 40% black pts; 4- and 6-wk arms had 40% to 44% and 20% to 24% pts with > 6 million IU/mL, respectively

Most pts in the F3-F4 fibrosis treatment groups had F3 fibrosis (64% to 68%)

Univariate analysis: HCV RNA < 6 million IU/mL and GT1b HCV predicted response

Kattakuzhy S, et al. EASL 2015. Abstract P0875.

Tx-naive GT1 pts withF0-F2 fibrosis

(N = 50)

LDV/SOF + GS-9451(n = 25)

LDV/SOF + GS-9451 + GS-9669(n = 25)

Nonrandomized

Tx-naive GT1 pts withF3-F4 fibrosis

(N = 25)

LDV/SOF + GS-9451(n = 25)

Tx-exp’d GT1 pts withF3-F4 fibrosis

(N = 25)

LDV/SOF + GS-9451(n = 25)

Wk 6Wk 4SVR12, %

Coformulated LDF/SOF 90/400 mg QD; GS-9451 80 mg QD; GS-9669 500 mg QD.

LTFU, % Relapse, %

Pts Not Achieving SVR12

40

20

68

80

0

4

8

0

60

76

24

20

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Short-Duration Sofosbuvir/GS-5816 + GS-9857 in GT1 HCV Pts Single-center, nonrandomized, open-label phase II trial

Key baseline characteristics

– IL28B CC: treatment-naive pts: noncirrhotic (33%), cirrhotics (53%); treatment-experienced pts (20%)

– 73% to 93% pts had GT1a HCV infection; 17% of pts in treatment-experienced group had cirrhosis

Gane EJ, et al. EASL 2015. Abstract LP03.

Sofosbuvir/GS-5816 + GS-9857 (n = 15)

Sofosbuvir/GS-5816 + GS-9857 (n = 15)Tx-naive noncirrhotic

GT1 pts (N = 30)

Sofosbuvir/GS-5816 + GS-9857 (n = 30)

Sofosbuvir/GS-5816 + GS-9857 (n = 15)

Wk 6Wk 4

Tx-naive cirrhotic GT1 pts (N = 30)

Tx-exp’d GT1 pts ± cirrhosis(N = 30)

Sofosbuvir/GS-5816 400 mg/100 mg FDC tablet QD; GS-9857 100 mg QD.

Page 30: EASL 2015. HCV Investigational Agents

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Short-Duration Sofosbuvir/GS-5816 + GS-9857: Efficacy Results

All pts who did not achieve SVR12 relapsed

SVR12 rates for treatment-experienced pts: no cirrhosis, 68% (17/25 pts); cirrhosis, 60% (3/5 pts)

Gane EJ, et al. EASL 2015. Abstract LP03.

SVR12, n/N (%)

Sofosbuvir/GS-5816 + GS-9857

Treatment Naive, No Cirrhosis

Treatment Naive, Cirrhosis

Treatment Experienced± Cirrhosis

4 wks 4/15 (27)

6 wks 14/15 (93) 13/15 (87) 20/30 (67)

Page 31: EASL 2015. HCV Investigational Agents

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Short-Duration Sofosbuvir/GS-5816 + GS-9857: Adverse Events

Gane EJ, et al. EASL 2015. Abstract LP03.

No serious adverse events or discontinuations for toxicity

9% experienced grade 3/4 laboratory abnormalities; 4 of 7 events constituted transient lipase elevations

Overall, adverse events occurred in 77% of pts

Adverse events occurring in ≥ 5% of pts (N = 75) included nausea (25%), headache (24%), fatigue (16%), diarrhea (9%), viral infection (7%), abdominal discomfort (5%), and mouth ulcers (5%)

Page 32: EASL 2015. HCV Investigational Agents

Evolving Options in Difficult-to-Treat Patients

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SOF + NS5A Inhibitors ± RBV in Pts With GT1/3 HCV and Decompensated Cirrhosis Observational cohort study of National Health Service of England (N = 467)

At physician’s discretion, pts received 12 wks SOF + LDV or DCV ± RBV

Baseline Characteristic

All Pts(N = 467)

Genotype 1(n = 235)

Genotype 3(n = 189)

Other Genotypes(n = 43)

CTP B, % 66.2 68.5 64.0 62.8

CTP C, % 9.9 8.1 12.7 7.0

Mean MELD score (range)

11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-22)

Regimen, % of total population

SOF + LDV + RBV 54.0 35.1 13.1 5.8

SOF + DCV + RBV 36.8 9.6 24.4 2.8

RBV-free regimen 9.2 5.6 3.0 0.6

Foster GR, et al. EASL 2015. Abstract O002. Reproduced with permission.

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N =

100

80

60

40

20

0

SOF + NS5A Inhibitors ± RBV in Pts With Decompensated Cirrhosis: Efficacy

Foster GR, et al. EASL 2015. Abstract O002. Reproduced with permission.

SVR12 among pts with other HCV GTs: 89% (n = 27) with SOF + LDV + RBV; 85% (n = 13) with SOF + DCV + RBV; 100% (n = 3) SOF + DCV

12-wk SOF + LDV + RBV

All GT1 GT3

SV

R12

, % (

ITT

)

P < .05

59

43

70 71

252 28 172 15 164 21 45 5 61 7 114 7

12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV

80 71 74 73

86 81 82

60

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SOF + NS5A Inhibitors ± RBV in Pts With Decompensated Cirrhosis: Safety

91% of pts received RBV

– 6% discontinued RBV

– 30% had hemoglobin ≤ 10 g/dL

Longer follow-up required to evaluate risk:benefit

– 20% reduced RBV dose

– 5% had hemoglobin ≤ 8 g/dL

Foster GR, et al. EASL 2015. Abstract O002. Reproduced with permission.

SAEs by Follow-up Wk 4Events,

n (% of All SAEs)Pts,

n (% of All Pts)

All SAEs 175 119 (26)

SAE likely related to liver disease and/or tx 138 (79) 100 (21)

Ascites 55 (31) 38 (8)

Hepatic encephalopathy 28 (16) 23 (5)

Infection 26 (15) 23 (5)

Liver transplantation -- 16 (3)

Death -- 14 (3)

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Compassionate Use Program: SOF + DCV ± RBV for GT3 HCV Infection Interim analysis of nonrandomized, multicenter, compassionate use program

Pts had GT3 HCV infection and ≥ F3 liver disease, extrahepatic manifestation of HCV disease, HCV recurrence following liver transplantation, or indication for liver or kidney transplantation (N = 601)

76% of pts were cirrhotic; 73% were treatment experienced

Pts received sofosbuvir + daclatasvir ± ribavirin for 12 or 24 wks

Treatment discontinuations to date

– Adverse events: n = 1; death: n = 2; pt decision: n = 1

Hezode C, et al. EASL 2015. Abstract LP05.

SVR4, % (n/N)12 Wks of Sofosbuvir + Daclatasvir ± Ribavirin

24 Wks of Sofosbuvir + Daclatasvir ± Ribavirin

Noncirrhotic pts 11/12 (92) 5/6 (83)

Cirrhotic pts 22/29 (76) 52/59 (88)

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ALLY-1: SOF + DCV + RBV in Cirrhotic or Posttransplant HCV-Infected Pts Multicenter, open-label phase III trial

Enrolled advanced cirrhosis (n = 60) or post–liver transplant (n = 53) pts

– 95% and 96% of pts were white, 40% and 42% were treatment naive, 75% and 77% were infected with GT1 HCV

Treatment

– All pts: 12 wks of daclatasvir 60 mg QD + sofosbuvir 400 mg QD + RBV

– Initial RBV dose 600 mg/day, adjusted to 1000 mg/day based on hemoglobin levels and creatinine clearance

– Pts with advanced cirrhosis who interrupted treatment due to liver transplantation could receive 12 additional wks of therapy immediately after transplantation

– Individuals relapsing following 12 wks of daclatasvir + sofosbuvir + RBV offered re-treatment with the same regimen for 24 wks

Poordad F, et al. EASL 2015. Abstract LO8.

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ALLY-1: Key Results

In subgroup analysis of pts in the advanced cirrhosis group, those who were Child-Pugh class C (n = 16) or had albumin < 2.8 g/dL (n = 18) had SVR12 rates of 56%

10/10 pts who relapsed in the advanced cirrhosis group had NS5A RAVs at virologic failure; 4 of 10 pts had NS5A RAVs at baseline

3/3 pts who relapsed in the posttransplantation group had NS5A RAVs at virologic failure; none had NS5A RAVs at baseline

Poordad F, et al. EASL 2015. Abstract LO8. Reproduced with permission.

Genotype

100

80

60

40

20

0

SV

R1

2 (

%)

All Pts

AdvancedCirrhosis

Post-transplant

50/60 50/53

8394

n/N =

4 6

Advanced Cirrhosis Cohort

4/4

100

26/34

76

1a 1b 2 3 4 6 1a 1b 2 3

11/11

100

4/5

80

5/6

83

0/0

30/31

97

9/10

90

0/0

10/11

91

0/0

1/1

100

Posttransplant Cohort

Child-Pugh Class

Advanced Cirrhosis Cohort

11/12

92

A B C

30/32

94

9/16

56

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ANRS CUPILT: SOF + DCV Treatment for HCV Recurrence After Liver Transplant Multicenter, open-label, nonrandomized study

SOF + DCV (n = 11)

SOF + DCV+ RBV(n = 3)

Pts with HCV recurrence posttransplant,

no coinfection with HIV(N = 130) SOF + DCV

(n = 64)

Wk 12

SOF + DCV+ RBV(n = 52)

Wk 24

SOF dosed 400 mg/day; DCV dosed 60 mg/day; renal function-based RBV dosing.Treatment type and duration at discretion of investigator; 3 pts in 24-wk groups received ≥ 36 wks of treatment.

Coilly A, et al. EASL 2015. Abstract G15.

Most pts were GT1a (27% to 29%) or GT1b (47% to 49%)

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SOF + DCV SOF + DCV + RBV

Naive 1a 1b 3 4 5 ≤ F2 F3 F4

96

ANRS CUPILT: Efficacy Results

From baseline to follow-up wk 24, albumin improved from 37 g/L to 40 g/L

Coilly A, et al. EASL 2015. Abstract G15. Reproduced with permission.

100

80

60

40

20

0

SV

R12

(%

)

Overall, Wk 24

97 96

Tx History Genotype Fibrosis Stage

Exp’d

96 97 97 97 91 91 100 93 98

65/68

60/62

35/36

61/63

10/11

10/11

1/1

44/46

27/29

39/40

62/64

50/52n/N =

All Pts

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ANRS CUPILT: Variation in Immunosuppressive Agent Dosing

Coilly A, et al. EASL 2015. Abstract G15. Reproduced with permission.

Cyclosporine Tacrolimus Everolimus MMF

Baseline/Wk 4100

80

60

40

20

0% V

aria

tio

n i

n D

osi

ng

4

-4

19

34

-5

21

0 2

Baseline/EOT

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ALLY-2: Daclatasvir + Sofosbuvir for HIV/HCV Coinfection Multicenter, randomized phase III study

Treatment arms well matched at baseline and GT1 HCV infection most prevalent (> 80% per arm)

Cirrhosis more common on treatment-experienced arm (29% vs 9% to 10% for treatment-naive arms)

Almost all pts received ART (atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, efavirenz, nevirapine, rilpivirine, raltegravir, dolutegravir, or NRTIs only)

Wyles DL, et al. EASL 2015. Abstract LP01.

Daclatasvir + Sofosbuvir(n = 101)

Daclatasvir + Sofosbuvir(n = 50)

HCV treatment-naive, HCV/HIV-coinfected

pts(n = 151)

Daclatasvir + Sofosbuvir(n = 52)

Daclatasvir 60 mg QD, with dose adjustment for ART use: 30 mg QD with ritonavir-boosted PIs, 90 mg QD with NNRTIs except rilpivirine. Sofosbuvir 400 mg QD.

Wk 8

HCV treatment-experienced, HCV/HIV-coinfected

pts(n = 52)

Wk 12

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ALLY-2: Key Results

No significant differences in SVR12 rates by HCV genotype, HCV disease characteristics, CD4+ cell count, or ART use in either 8-wk or 12-wk arms

Ongoing control of HIV disease maintained without need for ART modification

28 of 32 pts with NS5A RAVs achieved SVR12

– Among 4 pts with NS5A RAVS who did not achieve SVR12, 3 were in 8-wk arm

– Emergent NS5A Q30 RAVs detected in 3 of 13 pts with virologic failure

Wyles DL, et al. EASL 2015. Abstract LP01. Reproduced with permission.

Naive, 12 wks of DCV + SOFNaive, 8 wks of DCV + SOFExp’d, 12 wks of DCV + SOF

Genotype 1 All Treated

100

80

60

40

20

0

SV

R12

(%

)

96.475.6

97.7 97.076.0

98.1

80/83

31/41

43/44

98/101

38/50

51/52n/N =

Page 44: EASL 2015. HCV Investigational Agents

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