best of hcv from easl

1

Best of HCV from EASL

Savino Bruno, MDMilano, Italy

This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences

2

Abstract #O7

Once-Daily Simeprevir (TMC435) Plus Sofosbuvir (GS-7977) With or Without Ribavirin in HCV Genotype 1 Prior Null

Responders With Metavir F0-2: Cosmos Study Subgroup Analysis

M. Sulkowski1, I.M. Jacobson2, R. Ghalib3, M. Rodriguez-Torres4, Z. Younossi5, A. Corregidor6, B. Fevery7, K. Callewaert8, W. Symonds9, G. De La Rosa10, G. Picchio11, S. Ouwerkerk-Mahadevan8,

T. Lambrecht12, E. Lawitz13

1Johns Hopkins University School of Medicine, Baltimore, MD, 2Weill Cornell Medical College, New York, NY, 3Texas Clinical Research Institute, Arlington, TX, 4Fundaci_n de Investigaci_n, San Juan, PR,

5Department of Internal Medicine, Inova Fairfax Hospital, Falls Church, VA, 64800 Belfort Rd, Jacksonville, FL, United States, 7Janssen Research & Development, Janssen Infectious Diseases BVBA, Beerse,

Belgium, 8Janssen Research & Development, Beerse, Belgium, 9Gilead Sciences, Inc., Foster City, CA, 10Janssen Global Services, Raritan, NJ, United States, 11Novellas Healthcare, Zellick, Belgium, 12Janssen Research & Development, Titusville, NJ, 13The Texas Liver Institute, University of Texas Health Science

Center, San Antonio, TX, United States

3

• Cohort 1: METAVIR F0-F2, prior null responders to PR therapy– Stratified by IL28B, HCV GT 1 subtype

• Primary endpoint: SVR12

• Secondary endpoints included RVR and relapse rate

BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentSulkowski, M. et al. EASL 2014, Abstract #O7

COSMOS Study Design: Randomised, Multicentre, Open-label Trial

0 4 12 24 36 48Week

SMV + SOF + RBV Post-treatment follow-up

SMV + SOF Post-treatment follow-up

Post-treatment follow-up

Post-treatment follow-upSMV + SOF

Arm 1

Arm 2Randomised2:1:2:1

Arm 3

Arm 4

SMV + SOF + RBV

SMV 150 mg QD + SOF 400 mg QD±RBV 1000/1200 mg/day (BID)

4

93%96%

4% 7%

93%79%

17%

7%4%

COSMOS Cohort 1: SVR12 – Primary endpoint (ITT population)

24 weeks

SMV/SOF + RBV SMV/SOF

100

SVR12

Pro

por

tion

of p

atie

nts

(%)

1/24

4/24

12 weeks

Non-VF Relapse

1/15

80

60

40

20

014/1519/24 13/1426/27

SMV/SOF + RBV SMV/SOF

1001/14

1/27

80

60

40

20

0

ITT, intent-to-treat; Non-VF, Non-virologic failure, patients who did not achieve SVR12 for reasons other than virologic failureSulkowski, M. et al. EASL 2014, Abstract #O7

5

*Excluding patients who discontinued for non-virologic reasons

COSMOS Cohort 2: SVR12 by HCV GT 1 Subtype and Baseline NS3 Q80K Polymorphism (Excluding Non-VF*)

Sulkowski, M. et al. EASL 2014, Abstract #O7

0

20

40

60

80

100100 100 100 100 100100 100 100 100 100

89

100

8983

89

GT1b GT1a without Q80K GT1a with Q80K

SMV/SOF±RBV

SV

R12 (

%)

SMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF

24 weeks 12 weeks Overall

4/4 7/7 8/9 3/3 7/7 3/3 6/6 12/12 8/9 4/4 4/4 5/6 17/17 30/30 24/27

6

Conclusions

• SMV/SOF QD led to high SVR12 rates in HCV GT1-infected patients regardless of treatment duration or the addition of RBV

• SVR12 rates were high, regardless of baseline characteristics:– HCV GT1 subtype, Q80K polymorphism, IL28B genotype

• On-treatment virologic response, including RVR, was not predictive of SVR

• Two Phase 3 trials investigating SMV/SOF without ribavirin are ongoing (OPTIMIST-1 and -2)

GT, genotype; ITT, Intent-to-treat; QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentSulkowski, M. et al. EASL 2014, Abstract #O7

7

Abstract #O165

Simeprevir Plus Sofosbuvir With/Without Ribavirin inHCV Genotype-1 Prior Null-responder /

Treatment-naïve Patients (COSMOS Study): Primary Endpoint (SVR12) Results in Patients With METAVIR F3-4 (Cohort 2)

E. Lawitz1, R. Ghalib2, M. Rodriguez-Torres3, Z.M. Younossi4, A. Corregidor5, M.S. Sulkowski6,E. DeJesus7, B. Pearlman8, M. Rabinovitz9, N. Gitlin10, J.K. Lim11, P.J. Pockros12, B. Fevery13,T. Lambrecht14, S. Ouwerkerk-Mahadevan13, K. Callewaert13, W.T. Symonds15, G. Picchio16,

K. Lindsay16, M. Beumont-Mauviel13, I.M. Jacobson17

1Texas Liver Institute, San Antonio, 2Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, 3Fundacion de Investigacion, San Juan, PR, 4Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, 5Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, 6Johns Hopkins University School of Medicine, Baltimore, MD, 7Orlando Immunology Center, Orlando, FL, 8Atlanta Medical Center,

Atlanta, GA, 9University of Pittsburgh Medical Center, Pittsburgh, PA, 10Atlanta Gastroenterology Association, Atlanta, GA, 11Yale School of Medicine, New Haven, CT, 12Scripps Clinic, La Jolla, CA, United

States, 13Janssen Research & Development, Beerse, 14Novellas Healthcare, Zellik, Belgium, 15Gilead Sciences Inc, Foster City, CA, 16Janssen Research & Development LLC, Titusville, NJ, 17Weill Cornell

Medical College, New York, NY, United States

8

Non-VF, patients who did not achieve SVR12 for reasons other than virologic failureITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endBID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentLawitz, E. et al. EASL 2014, Abstract #O165

COSMOS Cohort 2: SVR12 – Primary Endpoint (ITT population)

0

20

40

60

80

1007% 7% 7%

SMV/SOF±RBV

Pro

po

rtio

n o

f p

atie

nts

(%

)



SVR12 Non-VF Relapse

93% 100% 93%93% 94%

2/30 1/142/27 3/872/87

28/30 16/16 13/1425/27 82/87

3%2%

9

*Excluding patients who discontinued for non-virologic reasons

GT 1a without Q80K

100 100

9388

95

GT 1a with Q80K

100 100

88

10096

SMV/SOF±RBV

SV

R12

(%

)



GT 1b

6/6 11/11 11/11 4/4 7/7 4/4 5/5 13/14 7/8 3/3 7/8 3/3 18/18 38/40 25/26

100

80

40

20

0

60

100 100 100 100 100

COSMOS Cohort 2: SVR12 by HCV GT 1 Subtype and Baseline NS3 Q80K Polymorphism (Excluding Non-VF*)

GT, genotype; non-VF, non-virologic failure; RBV, ribavirinSMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologicresponse 12 weeks after planned treatment endLawitz, E. et al. EASL 2014, Abstract #O165

10

Conclusions

• SMV/SOF QD led to SVR12 rates of 93-100% (ITT) in HCV GT 1 infected treatment-naïve and prior null-responder patients with METAVIR F3-4

• SVR12 rates were high, regardless of baseline characteristics:

– HCV GT 1 subtype, Q80K polymorphism, METAVIR score, IL28B GT, prior treatment history

• SMV/SOF QD +/- RBV was safe and well tolerated

• Two Phase 3 trials investigating SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2)

Lawitz, E. et al. EASL 2014, Abstract #O165

11

Abstract #O68

Sofosbuvir and Ribavirin for the Treatment of Chronic HCV With Cirrhosis and Portal Hypertension With and Without Decompensation: Early Virologic Response and Safety

Nezam Afdhal,1 Gregory Everson,2 Jose Luis Calleja,3 Geoffrey McCaughan,4 William T. Symonds,5

Diana Brainard,5 Jill Denning,5 Theo Brandt-Sarif,5 Lindsay McNair,5 John G. McHutchison,5

Sarah Arterburn,5 Jaime Bosch,10 Michael Charlton,6 Rajender Reddy,7 Tarik Asselah,8 Edward Gane,9 Xavier Forns10

1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2University of Colorado Denver, Aurora, CO, USA; 3Hospital Puerta de Hierro, Madrid, Spain; 4Royal Prince Alfred Hospital, University of Sydney, New

South Wales, Australia; 5Gilead Sciences, Inc., Foster City, CA, USA; 6Mayo Clinic, Rochester, MN, USA;7University of Pennsylvania, Philadelphia, PA, USA; 8Hopital Beaujon, INSERM U 773 and University Paris-Diderot, Clichy, France; 9Auckland City Hospital, Grafton, Auckland, New Zealand; 10Hospital Clinic,

Institut d’Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain

12

Study Design and Aim

• Aim: To explore the safety and efficacy of SOF+RBV in HCV-infected patients with portal hypertension ± decompensated liver disease

• Primary objective: SVR12• Secondary objectives

– Effects of 48 weeks of treatment on hepatic portal pressure and function– Safety and clinical improvement as measured by clinical outcomes, CPT, MELD, and

biochemical test results

Study results through the first 24 weeks are presented

Afdhal, N. et al. EASL 2014, Abstract #O68

SOF 400 mg + RBV 1000-1200 mgSVR 12

SOF 400 mg + RBV 1000-1200 mg

Wk 0 Wk 24 Wk 48 Wk 96Wk 72

HVPG at Day 0 and Week 48

HVPG at Day 0, and Weeks 24 and 72

Arm 1N=25

Arm 2N=25

SVR 12

Observation

13

*1 patient was a non-responder at Week 8.Afdhal, N. et al. EASL 2014, Abstract #O68

Results: Virologic Response on Treatment

2 4 8 12 240

20

40

60

80

100

56

100 100 100 100

44

75

94* 94 93

CPT A CPT B

Week

HC

V R

NA

< L

LO

Q (

%)

5/9 7/16 9/9 12/16 8/8 15/16 8/8 15/16 7/7 14/15

14

Conclusions

• In HCV-infected patients with portal hypertension with and without hepatic decompensation, treatment with SOF+RBV for up to 24 weeks resulted in:– High rates of virologic suppression irrespective of severity of

liver disease– Decreased necroinflammation with ALT normalization– Improvements in platelet count and albumin– Improvement in ascites and hepatic encephalopathy

• SOF+RBV for up to 24 weeks was generally safe and well tolerated with low rates of treatment discontinuation due to AEs– No patients developed worsening or new onset hepatic

decompensation

Afdhal, N. et al. EASL 2014, Abstract #O68

15

Abstract #O6

Sofosbuvir/Ledipasvir Fixed Dose Combination is Safe and Effective in Difficult-to-treat Populations Including Genotype-3

Patients, Decompensated Genotype-1 Patients, and Genotype-1 Patients With Prior Sofosbuvir Treatment Experience

E.J. Gane1, R.H. Hyland2, D. An2, P.S. Pang2, W.T. Symonds2, J.G. McHutchison2, C.A. Stedman3

1Auckland Clinical Studies, Auckland, New Zealand; 2Gilead Sciences, Inc., Foster City, CA, United States; 3Christchurch Clinical Studies Trust, Christchurch, New Zealand

16

Wk 0 Wk 12 Wk 24

SVR12

LDV/SOF + RBV, n=26

LDV/SOF, n=25GT 3

Treatment naïve

Ra

nd

om

ize

d

ELECTRON-2: Study Design

1. HCV GT 1, relapsed after previous treatment with SOF-containing regimens in ELECTRON-1

2. HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B)

3. HCV GT 3, treatment naïve

LDV/SOF + RBV, n=19GT 1

Prior SOF exposure

GT 1CPT class B LDV/SOF, n=20

Gane, E. et al. EASL 2014, Abstract #O6

17

19/19

SV

R12

(%

)

Re-treatment

GS-9669 + SOF+RBV 12 wk

Treatment Naïve

SOF+RBV 12 wk Prior Null

Responders

n=6

n=4

n=8

n=1

LDV/SOF +RBV 6 wk

Treatment Naïve

SOF+RBV 12 wk Treatment Naïve

19/19

ELECTRON-2 Results:(1) Prior Sofosbuvir-Treated GT 1 Patients

• All 19 previous SOF-regimen failures had relapsed


18

SV

R12

(%

)13/20

GT 1CPT Class B

Median total bilirubin,mg/dL (range)

1.5 (0.7-3.7)

Median serum albumin,g/dL (range)

3.1 (2.3-3.8)

Median INR (range)

1.2 (1.0-3.0)

Ascites, n (%) 4 (20)

Hepatic encephalopathy,

n (%)6 (30)

Median platelet count,103/µL (range)

84 (44-162)

7 relapsers


Error bar represents the 95% confidence interval.

ELECTRON-2 Results:(2) Patients With CPT B Cirrhosis

19

SV

R12

(%

)

16/25 26/26

100

64*

0

20

40

60

80

100

LDV/SOF + RBV 12 Weeks

26/2616/25

LDV/SOF 12 Weeks

*Failure due to relapse (n=8) or discontinuation due to AE (n=1)Gane, E. et al. EASL 2014, Abstract #O6

ELECTRON-2 Results:(3) Patients With HCV GT 3, Treatment Naïve

20Gane, E. et al. EASL 2014, Abstract #O6

LDV/SOF regimens for 12 weeks are safe and effective IFN-free treatments for many diverse and difficult-to-treat patient populations including:

• Patients infected with HCV GT 1 who have failed previous SOF-containing regimens

• Patients infected with HCV GT 1 with decompensated cirrhosis

• Patients infected with HCV GT 3

ELECTRON-2 Conclusions

21

Abstract #O1

SAPPHIRE II: Phase 3 Placebo-Controlled Study Of Interferon-Free, 12-Week Regimen Of ABT-450/r/ABT-267,

ABT-333, And Ribavirin In Treatment-Experienced Adults With Hepatitis C Virus Genotype 1

S. Zeuzem1, I. Jacobson2, T. Baykal3, R.T. Marinho4, F. Poordad5, M. Bourliere6, M. Sulkowski7, H. Wedemeyer8, E. Tam9, P. Desmond10, D. Jensen11, A.M. Di Bisceglie12, P. Varunok13, T. Hassanein14, J.

Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3

1J.W. Goethe University, Frankfurt, Germany, 2Weill Cornell Medical College, New York, NY, 3AbbVie Inc., North Chicago, IL, United States, 4Centro Hospitalar de Lisboa Norte, Lisbon, Portugal, 5The Texas Liver

Institute, University of Texas Health Science Center, San Antonio, TX, United States, 6Hopital Saint Joseph, Marseille, France, 7Johns Hopkins University, Baltimore, MD, United States, 8Medizinische Hochschule

Hannover, Hannover, Germany, 9LAIR Centre, Vancouver, BC, Canada, 10St Vincent's Hospital (Melbourne), Fitzroy, VIC, Australia, 11Center for Liver Diseases, University of Chicago Medical Center Chicago, Chicago,

IL, 12Saint Louis University, St. Louis, MO, 13Premier Medical Group of the Hudson Valley, PC, Poughkeepsie, NY, 14Southern California Liver Centers and Southern California Research Center,

Coronado, CA, United States

22

SAPPHIRE-II: Placebo-Controlled Design (N=394)

• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID

• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively)

Week 0 Week 12 Week 24 Week 60 Week 72

3D + RBV(n=297)

Placebo(n=97) 3D + RBV

Double-BlindTreatment Period

Open-LabelTreatment Period

48-WeekFollow-Up

48-WeekFollow-Up

Primary Analysis: SVR12

Zeuzem, S. et al. EASL 2014, Abstract #O1

23

3D + RBV(N=297)

Placebo(N=97)

Male / female, n (%) 167 (56.2) / 130 (43.8) 60 (61.9) / 37 (38.1)

White, n (%) 269 (90.6) 86 (88.7)

Median age, years (range) 54.0 (19.0-71.0) 56.0 (30.0-69.0)

Median BMI, kg/m2 (range) 26.0 (18.1-38.1) 26.1 (18.5-36.7)

Fibrosis stage, n (%)

F0-F1 202 (68.0) 65 (67.0)

F2 53 (17.8) 17 (17.5)

F3 42 (14.1) 15 (15.5)

IL28B* non-CC genotype, n (%) 263 (88.6) 90 (92.8)

HCV subtype, n (%)

1a 173 (58.2) 57 (58.8)

1b 123 (41.4) 40 (41.2)

Median HCV RNA, log10 IU/mL (range) 6.66 (4.61-7.70) 6.55 (5.20-7.55)

Prior pegIFN/RBV response, n (%)

Relapse 86 (29.0) 29 (29.9)

Partial response 65 (21.9) 21 (21.6)

Null response 146 (49.2) 47 (48.5)

*IL28B rs12979860 HCV genotype and subtype assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0.HCV RNA level measured by COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, v2.0 (Roche).Zeuzem, S. et al. EASL 2014, Abstract #O1

SAPPHIRE-II: Baseline Patient Characteristics

24Zeuzem, S. et al. EASL 2014, Abstract #O1

SAPPHIRE-II Results: ITT SVR12 Rates (Superior to Placebo)

0

20

40

60

80

100S

VR

12,

% P

ati

ents

All Patients

96.3% 96.0% 96.7%

286/297 166/173 119/123

GT1a GT1b

25Zeuzem, S. et al. EASL 2014, Abstract #O1

SAPPHIRE-II Results: ITT SVR12 Rates >95% in All Prior PEG/RBV Response Groups

0

20

40

60

80

100S

VR

12,

% P

ati

ents

PriorRelapse

95.3% 100% 95.2%

82/86 65/65 139/146

PriorPartial

Response

PriorNull

Response

26

SAPPHIRE-II: Conclusions

• The ITT SVR12 rate was 96.3% (286/297) for treatment-experienced GT1-infected patients receiving 12 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV

• High SVR12 rates regardless of HCV subtype and across all prior pegIFN/RBV response groups

• The regimen was generally well-tolerated, with a low rate of study drug discontinuation due to AE(s) (1.0%)

Zeuzem, S. et al. EASL 2014, Abstract #O1

27

Abstract #O163

TURQUOISE-II:SVR12 Rate of 92-96% in 380 Hepatitis C Virus Genotype 1-infected Adults With Compensated

Cirrhosis Treated With ABT-450/R/ABT-267 and ABT-333 Plus Ribavirin

F. Poordad1, C. Hezode2, R. Trinh3, K.V. Kowdley4, S. Zeuzem5, K. Agarwal6, M.L. Shiffman7, H. Wedemeyer8, T. Berg9, E.M. Yoshida10, X. Forns11, S.S. Lovell3, B. Da Silva-Tillmann3, A.L. Campbell3,

T. Podsadecki3

1The Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2Henri Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3AbbVie Inc., North

Chicago, IL, 4Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5J.W. Goethe University, Frankfurt, Germany, 6Institute of Liver Studies, Kings College Hospital, London, United

Kingdom, 7Liver Institute of Virginia, Newport News, VA, United States, 8Medizinische Hochschule Hannover, Hannover, 9Universit_tsklinikum Leipzig, Leipzig, Germany, 10University of British Columbia,

Vancouver, BC, Canada, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

28

TURQUOISE-II Study Design: Phase 3 Trial Conducted Exclusively in GT1-Infected Cirrhotic Patients (N=380)

• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID

• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively)

Day 0 Week 24Week 12

SVR12

SVR12

3D + RBV(N=208)

3D + RBV(N=172)

Poordad, F. et al. EASL 2014, Abstract #O163

29

TURQUOISE-II:Demographics and Patient Characteristics

12-Week Arm(N=208)

24-Week Arm(N=172)

Male (%) 70.2 70.3

White race (%) 95.7 93.6

Hispanic or Latino ethnicity (%) 12.0 11.6

Mean age (years) 57.1 56.5

Mean BMI (kg/m2) 27.9 27.9

IL28B non-CC (%) 83.2 80.2

HCV genotype 1a (%) 67.3 70.3

Treatment-naïve (%) 41.3 43.0

Treatment-experienced (%) 58.7 57.0

Relapse 13.9 13.4

Partial responder 8.7 7.6

Null responder 36.1 36.0

Platelet count <100 x 109/L (%) 21.6 19.2

Serum albumin <3.5 g/dL (%) 12.0 10.5

Child-Pugh score >5 (%) 18.3 18.6

3D + RBV


30

TURQUOISE-II Results:ITT SVR12 Rates of 92% to 96%

0

20

40

60

80

100

SV

R12

, %

Pat

ien

ts

12 Weeks3D + RBV

91.8

191/208

95.9

165/172

24 Weeks3D + RBV

P=0.089


31

TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a

0

20

40

60

80

10092.2 92.9

Naïve Prior RelapseResponse

SV

R12

, %

Pat

ien

ts

59/64 14/1552/56 13/13

93.3 100 100 100 80.0 92.9

11/11 40/5010/10 39/42

Prior PartialResponse

Prior NullResponse

HCV Subtype 1a

12-week arm

24-week arm

3D + RBV


32

TURQUOISE-II: Conclusions

• First dedicated trial of IFN-free regimen in cirrhotic patients, including patients often ineligible for clinical trials (low platelets, low albumin, radiographic ascites)

• SVR rates of 92% to 96% with 12 and 24 weeks of treatment, with high SVR rates in all subgroups analyzed

• 12 or 24 weeks of treatment were similarly well tolerated, with low rates of treatment discontinuation

• Efficacy and safety in this large cirrhotic population is similar to non-cirrhotics treated with the same regimen


33

Abstract #P1299

PEARL-III: 12 Weeks of ABT-450/R/267 + Abt-333 Achieved SVR in >99% of 419 Treatment-Naïve HCV Genotype 1b-

Infected Adults With or Without Ribavirin

P. Ferenci1, A. Nyberg2, P. Enayati3, D. Bernstein4, Y. Baruch5, F.A. Caruntu6, V. Chulanov7, E. Janczewska8, Z. Younes9, R.T. Marinho10,

G.Rizzardini11, J. Gervain12, R. Planas13, C. Moreno14, W. Xie15, D.Cohen15, M. King15, T. Podsadecki15, K.R. Reddy16

1Universitaetsklinik fuer Innere Medizin III, Vienna, Austria, 2KaiserPermanente, San Diego, 3California Liver Institute, Los Angeles, 4North Shore University Hospital, Manhasset, CA, United States,

5Rambam Health Care Campus, Haifa, Israel, 6Institutul National de Boli Infectioase 'Prof. Dr. Matei Bals', Bucharest, Romania, 7Federal Budget Institute of Science Central Research Institute of Epidemiology,

Moscow, Russian Federation, 8ID Clinic, Mysłowice, Poland,9GastroOne, Germantown, TN, United States, 10Centro Hospitalar Lisboa Norte, Lisboa, Portugal, 11Ospedale Luigi Sacco, Milano, Italy, 12Szent György Hospital, Székesfehérvár, Hungary, 13Hospital Germans Trías i Pujol, CIBERehd, Badalona, Spain, 14CUB

Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, 15AbbVie Inc., North Chicago, IL, 16University of Pennsylvania, Philadelphia, PA, United States

34

Figure 1 – PEARL III Study Design

• All patients received the 3D regimen– ABT-450/r/ombitasvir: 150 mg/100 mg/25 mg QD– Dasabuvir: 250 mg BID– RBV 1000 mg if body weight was <75 kg, 1200 mg if body weight ≥75 kg

(divided BID), or matching placebo

ABT-450/r/Ombitasvir + Dasabuvir + RBV

ABT-450/r/Ombitasvir + Dasabuvir + Placebo for RBV

3D + RBVN = 210

3D N = 209

Study drug dosingAssess for

SVR12

48-wkFollow-up

Day 0 Week 12 Week 24 Week 60

Ferenci, P. et al. EASL 2014, Abstract #P1299

35

Figure 2. SVR12 Rates After 12 Weeks of 3D ± RBV

Ferenci, P. et al. EASL 2014, Abstract #P1299

SV

R1

2, %

Pa

tien

ts

99.5 99.0

Superiority 84%Noninferiority 73%

3D + RBV 3D

100

80

60

40

20

0209/210 207/209

36

Conclusions

• SVR12 rates of 99.5% and 99% were achieved in treatment-naïve non-cirrhotic patients with GT1b infection following 12-week treatment with ABT-450/r/ombitasvir and dasabuvir with and without RBV, respectively

• 1 of 419 patients experienced virologic failure

• No patient discontinued prematurely due to adverse events in either treatment group

• Hematologic abnormalities and some adverse events were less frequent in the absence of RBV

• The addition of RBV in this population did not provide additional clinical benefit

37

Abstract #O166

All-Oral Dual Therapy With Daclatasvir and Asunaprevir in Patients With

HCV Genotype 1b Infection: Phase 3 HALLMARK-DUAL Study Results

M. Manns1, S. Pol2, I. Jacobson3, P. Marcellin4, S. Gordon5, C.-Y. Peng6, T.-T. Chang7, G. Everson8, J. Heo9, G. Gerken10, B. Yoffe11, W.J. Towner12, M. Bourliere13, S. Metivier14, C.-J. Chu15, W. Sievert16, J.-P. Bronowicki17, D. Thabut18, Y.-J. Lee19, J.-H. Kao20, F. McPhee21, J. Kopit21, P. Mendez22, M. Linaberry22,

E. Hughes22, S. Noviello22, HALLMARK DUAL Study Team

1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, 2H_pital Cochin, Paris, France, 3Weill Cornell Medical College, New York, NY, United States, 4Hopital Beaujon, Clichy, France, 5Henry Ford Health Systems, Detroit, MI, United States, 6School of Medicine, China Medical University, Taichung, 7National Chen Kung University Hospital, Tainan, Taiwan, 8University Of Colorado Denver, Aurora, CO, United States, 9Pusan National University Hospital, Busan, Korea, Republic of,

10University of Duisburg-Essen, Essen, Germany, 11VAMC, Baylor College of Medicine, Houston, TX, 12Kaiser Permanente, Los Angeles, CA, United States, 13Hopital Saint Joseph, Marseille, 14CHU Purpan, Toulouse, France, 15Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, 16Monash Health and Monash University, Melbourne, VIC, Australia, 17INSERM Unit_ 954, Centre Hospitalier Universitaire de Nancy and Universit_ de Lorraine, Vandoeuvre-l_s-Nancy, 18Hopital Piti_-Salp_tri_re, Paris, France, 19Inje

University Busan Paik Hospital, Busan, Korea, Republic of, 20National Taiwan University Hospital, Taipei, Taiwan, 21Bristol-Myers Squibb Research and Development, Wallingford, CT, 22Bristol-Myers Squibb Research and Development, Princeton, NJ, United States

38

Global Phase 3 Study: HALLMARK-DUAL (AI447-028)

• Primary endpoint: proportion of DCV + ASV-treated patients with SVR12

• Patients infected with HCV genotype 1b– Treatment-naïve– Nonresponders: prior null or partial response to pegIFN/RBV– Interferon-ineligible/intolerant (treatment-naïve or -experienced) due to

• Depression• Anemia/neutropenia• Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia

Ran

dom

izat

ion

2:1

STOP

DCV + ASV 24 weeks(N = 205)

DCV + ASV 24 weeks(N = 235)

Week 24 Week 48Day 1 Week 12

Nonresponder

Ineligible/intolerant

Treatment-naïve

DCV 60 mg QD + ASV 100 mg BID 24 weeks(N = 203)a

DCV-PBO + ASV-PBO 12 weeks (N = 102)

Enter another study:DCV + ASV 24 weeks

Follow up 24 weeks

Follow up 24 weeks

Follow up 24 weeks

SVR12

a Excludes 2 patients inadvertently assigned, instead of randomized, to DCV + ASV; patients were excluded from efficacy analyses but both achieved SVR12

Manns, M. et al. EASL 2014, Abstract #O166

39

0

20

40

60

80

100 9082 82

Virologic Response: SVR12

Treatment-naïve

Nonresponders Ineligible/intolerant

SV

R12

(%

of

pat

ien

ts)a,

b

• SVR12 rates documented on or after posttreatment Week 12– Treatment-naïve: 91%– Nonresponders: 82%– Ineligible/intolerant: 83%

a HCV RNA < lower limit of assay quantitation (25 IU/mL)b Patients with missing SVR12 data counted as treatment failuresManns, M. et al. EASL 2014, Abstract #O166

182/203 168/205 192/235

40

All-Oral Dual Therapy with Daclatasvir and Asunaprevir in Patients with HCV Genotype 1b Infection: A Phase 3 Study Results

Overall Cirrhotics Non cirrhotics0

10

20

30

40

50

60

70

80

90

10090 91 89

8287

808279

84

NaiveNull/Partial respondersIneligible/Intolerant

182/203 168/205 192/235 29/32 55/63 88/111 153/171 113/142 104/124

SV

R12

(%

)


41

Summary• All-oral DCV + ASV therapy achieved SVR12 rates up to

91% in treatment-naïve, 82% in nonresponder, and 83% in ineligible/intolerant patients with genotype 1b

– SVR12 rates were similar in non-cirrhotic (85%) and cirrhotic (84%) patients

– No differences by age, gender, race, IL28B genotype, or prior IFN/RBV treatment experience

• DCV + ASV was generally safe and well tolerated– Only 2% of patients discontinued treatment due to adverse events

• DCV is being further evaluated in all-oral combinations in multiple patient populations of high unmet need


42

Abstract #O61

Efficacy and Safety of MK-5172 And MK-8742 ± RIBAVIRIN IN Hepatitis C Genotype 1 Infected Patients

With Cirrhosis Or Previous Null Response: The C-WORTHY Study

E. Lawitz1, C. Hezode2, E. Gane3, E. Tam4, M. Lagging5, L. Balart6, L. Rossaro7, R. Ghalib8, M. Shaughnessy9, P. Hwang9, J. Wahl9, M.N. Robertson9, B. Haber9

1The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States, 2Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, France, 3Auckland Clinical Studies, Grafton, Auckland, New Zealand, 4LAIR Centre, Vancouver, BC,

Canada, 5Department of Infectious Disease, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden, 6Gastroenterology & Hepatology, Tulane University Medical Center, New Orleans, LA, 7Gastroenterology and Hepatology, University of California, Davis Medical Center, Sacramento, CA,

8Texas Clinical Research Institute, Arlington, TX, 9Merck, Whitehouse Station, NJ, United States

43

C-WORTHy:Treatment-Naïve Cirrhotics and Nulls

• Aim: To assess the efficacy, safety and optimal treatment duration of MK-5172 + MK-8742 ± ribavirin in patients with HCV genotype 1 infection who are: – Treatment naïve with cirrhosis; or– Null responders to prior peginterferon/ribavirin (PR) ± cirrhosis

Treatment-naïve Non-cirrhotic

8-12 weeks ± RBV(n = 94)

Treatment-naïve Cirrhotic

12-18 weeks ± RBV(n = 123)

HIV/HCV co-infectedNon-cirrhotic

12 weeks ± RBV(n = 59)

Null responders Cirrhotic / Non-cirrhotic

12-18 weeks ± RBV(n = 130)

Key eligibility criteria:• Treatment-naïve patients ≥18 years old with chronic HCV GT1a or GT1b infection• Null response = <2 log10 decline from baseline in HCV RNA after 12 weeks of prior PR• Liver biopsy or noninvasive test• Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males)• HIV and HBV negative• ALT and AST <350 IU/L• Albumin ≥3.0 g/dL; platelets ≥70,000/mm3


44

Efficacy of MK-5172 + MK-8742 ± RBVin Treatment-Naïve Patients with Cirrhosis: 12 vs 18 Weeks

0

10

20

30

40

50

60

70

80

90

10090

9790

100 10097

100 97 9790

100 97

12 wk, + RBV (n=31)

12 wk, No RBV (n=29)

18 wk, + RBV (n=32)


% P

atie

nts

HC

V R

NA

<2

5 I

U/m

L

2831

2831

32 32

2929

Breakthrough

3031

3131

31 32

2929

2831

2930*

30 31*

2829

TW4 TW12 FU4/8Relapse

Discontinuation• *Excludes patients who have not yet reached the FU4 time point• 12 week arms include 97% of FU8 results


45

0

10

20

30

40

50

60

70

80

90

100 94 94 94100 100

9197 100 100

94 97 97 12 wk, + RBV (n=32)


18 wk, + RBV (n=33)

18 wk, No RBV (n=32)%

Pa

tie

nts

HC

V R

NA

<2

5 I

U/m

L

3032

3032

32 33

3333

3032

3132

33 33

3333

3032

2930*

3232*

3033

TW4 TW12 FU4/8

Efficacy of MK-5172 + MK-8742 ± RBV in PR-Null Patients ± Cirrhosis: 12 vs 18 weeks

• *Excludes patients who have not yet reached the FU4 time point• 12 week arms include 97% of FU8 results


Breakthrough

Relapse

Discontinuation

46

Summary/ConclusionEfficacy

• MK-5172 + MK-8742 ± RBV demonstrated high efficacy:– 90-97% of cirrhotic patients achieved SVR4/8– 91-100% of prior null responders achieved SVR4/8

• In treatment-naïve patients with cirrhosis, high efficacy was achieved regardless of use of RBV or extended treatment duration

• In prior null-responder patients, a 12-week RBV-free regimen resulted in >90% SVR4/8

Safety• All treatment regimens were generally safe and well-

tolerated

These results support the ongoing Phase 3 development of MK-5172 + MK-8742 ± RBV in various patient populations


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