1 stefan zeuzem, md frankfurt, germany this activity is supported by an independent medical...

1

Best of HCV from EASL

Stefan Zeuzem, MDFrankfurt, Germany

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

2

Abstract #O165

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

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

Eric Lawitz,1 Reem Ghalib,2 Maribel Rodriguez-Torres,3 Zobair M Younossi,4 Ana Corregidor,5

Mark S Sulkowski,6 Edwin DeJesus,7 Brian Pearlman,8 Mordechai Rabinovitz,9 Norman Gitlin,10

Joseph K Lim,11 Paul J Pockros,12 Bart Fevery,13 Tom Lambrecht,14 Sivi Ouwerkerk-Mahadevan,13 Katleen Callewaert,13 William T Symonds,15 Gaston Picchio,16 Karen Lindsay,17

Maria Beumont-Mauviel,13 Ira M Jacobson18

1The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 2Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, USA; 3Fundación de

Investigación, San Juan, Puerto Rico, USA; 4Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; 5Borland-Groover Clinic, Jacksonville, FL, USA; 6Johns Hopkins University School of Medicine,

Baltimore, MD, USA; 7Orlando Immunology Center, Orlando, FL, USA; 8Atlanta Medical Center, Atlanta, GA, USA; 9University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 10Atlanta Gastroenterology Association, Atlanta, GA, USA; 11Yale School of Medicine, New Haven, CT, USA; 12Scripps Clinic, La Jolla, CA, USA;

13Janssen Research & Development, Beerse, Belgium; 14Novellas Healthcare, Zellik, Belgium; 15Gilead Sciences Inc, Foster City, CA, USA; 16Janssen Research & Development LLC, Titusville, NJ, USA;

17Formerly of Janssen Research & Development LLC, Titusville, NJ, USA; 18Weill Cornell Medical College, New York, NY, USA

3

• Cohort 1: METAVIR F0-F2, prior null responders• Cohort 2: METAVIR F3-F4, prior null responders or treatment-naïve

– Stratified by treatment history, HCV GT 1a/1b

• Primary endpoint: SVR12 • Secondary endpoints: RVR, on-treatment failure, relapse rate, safety and tolerability

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

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

ITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endNon-VF, patients who did not achieve SVR12 for reasons other than virologic failureLawitz, 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

(%

)

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

24 weeks 12 weeks Overall

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%

5

GT 1b

*Excluding patients who discontinued for non-virologic reasonsGT, genotype; non-VF, non-virologic failure; RBV, ribavirin SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endLawitz, E. et al. EASL 2014, Abstract #O165

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

SMV/SOF±RBV

SV

R12

(%

)

SMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF24 weeks 12 weeks Overall

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

6

GT 1b


COSMOS Cohort 2: SVR12 by HCV GT 1 Subtype And Baseline NS3 Q80K Polymorphism (Excluding Non-VF*) GT 1a without Q80K

100 100

9388

95

SMV/SOF±RBV

SV

R12

(%

)


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

7

GT 1b


COSMOS Cohort 2: SVR12 by HCV GT 1 Subtype And Baseline NS3 Q80K Polymorphism (Excluding Non-VF*) GT 1a without Q80K

100 100

9388

95

GT 1a with Q80K

100 100

88

10096

SMV/SOF±RBV

SV

R12

(%

)


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

8

COSMOS Cohort 2: SVR12 by METAVIR Score(excluding non-VF*)

*Excluding patients who discontinued for non-virologic reasonsNon-VF, non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endLawitz, E. et al. EASL 2014, Abstract #O165

0

20

40

60

80

100100 100

94

10098

100 100

9186

95

SMV/SOF±RBV

SV

R12

(%

)

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

24 weeks 12 weeks Overall

16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39

F3 F4

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*Excluding patients who discontinued for non-virologic reasonsNon-VF, non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endLawitz, E. et al. EASL 2014, Abstract #O165

COSMOS Cohort 2: SVR12 by TreatmentHistory – METAVIR F4 Patients (Excluding Non-VF*)

0

20

40

60

80

100100 100

80

10096

100 100 100

67

94

SMV/SOF±RBV

SV

R12

(%

)


9/9 3/3 4/4 5/5 4/5 6/6 4/4 2/3 21/22 16/17

Null responders Treatment naïves

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Abstract #O164

All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With Or Without Ribavirin for 12 or 24 Weeks in

Treatment-Naive Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study

Alessandra Mangia,1 Patrick Marcellin,2 Paul Kwo,3Graham R. Foster,4 Maria Buti,5 Norbert Bräu,6 Andrew Muir,7 Jenny C. Yang,8 Hongmei Mo,8 Xiao Ding,8 Phil S. Pang,8 William T. Symonds,8

John G. McHutchison,8 Stefan Zeuzem,9 Nezam Afdhal10

1Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 2Centre Hospitalier Universitaire Beaujon, Clichy-sous-Bois, France; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Queen

Mary’s University of London, Barts Health, UK; 5Hospital Universitario Valle de Hebrón, Barcelona, Cataluña, Spain; 6Mount Sinai School of Medicine, New York, NY, USA; 7Duke University Medical Center,

Durham, NC, USA;6Gilead Sciences, Inc., Foster City, CA; 9Johann Wolfgang Goethe University, Frankfurt, Germany; 10Beth Israel Deaconess Medical Center, Boston, MA, USA

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• GT 1 HCV treatment-naïve patients in Europe and USA• Broad inclusion criteria

– Targeted 20% enrollment of patients with cirrhosis– No upper age or BMI limit– Platelet count ≥50,000/mm3, no neutrophil minimum

• 865 patients randomized 1:1:1:1 across four arms • Stratified by HCV subtype (1a or 1b) and cirrhosis

Wk 0 Wk 12 Wk 36Wk 24

LDV/SOF SVR12

LDV/SOF + RBV

LDV/SOF

LDV/SOF + RBV

SVR12

SVR12

SVR12

Mangia, A. et al. EASL 2014, Abstract #O164

Study DesignGT 1 Treatment-Naïve (ION-1)

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• Arms were balanced with respect to demographics and baseline characteristics

12 Weeks 24 Weeks

LDV/SOFn=214

LDV/SOF+RBVn=217

LDV/SOFn=217

LDV/SOF+RBVn=217

Mean age, y (range) 52 (18–75) 52 (18–78) 53 (22–80) 53 (24–77)

Male, n (%) 127 (59) 128 (59) 139 (64) 119 (55)

Black, n (%) 24 (11) 26 (12) 32 (15) 26 (12)

Hispanic, n (%) 26 (12) 20 (9) 29 (13) 26 (12)

Region Europe 89 (42) 99 (46) 85 (39) 80 (37)

Mean BMI, kg/m2 (range) 27 (18–41) 27 (18–42) 27 (18–48) 26 (18–48)

Cirrhosis 34 (16) 33 (15) 33 (15) 36 (17)

IL28B CC, n (%) 55 (26) 76 (35) 52 (24) 73 (34)

Interferon ineligible 14 (7) 20 (9) 19 (9) 14 (7)

GT 1a, n (%) 144 (67) 148 (68) 146 (67) 143 (66)

Mean HCV RNA,log10 IU/mL (range) 6.4 (1.6–7.5) 6.4 (4.4–7.6) 6.3 (3.7–7.4) 6.3 (3.2–7.5)

HCV RNA ≥800,000 IU/mL 169 (79) 173 (80) 168 (77) 173 (80)


Results: Overall DemographicsGT 1 Treatment-Naïve (ION-1)

13

USAN=512

EuropeN=353

Mean age, y (range) 54 (19–77) 51 (18–80)

Male, n (%) 328 (64) 185 (52)

Black, n (%) 100 (20) 8 (2)

Hispanic, n (%) 45 (9) 56 (16)

Mean BMI, kg/m2 (range) 28 (18–48) 25 (18–37)

Cirrhosis 81 (16) 55 (16)

IL28B CC, n (%) 158 (31) 98 (28)

Interferon ineligible 43 (8) 24 (7)

GT 1a, n (%) 372 (73) 209 (59)

Mean baseline HCV RNA,log10 IU/mL (range) 6.3 (1.6–7.5) 6.4 (3.2–7.6)

Baseline HCV RNA≥800,000 IU/mL

399 (78) 284 (80)


Results: USA and European Patients DemographicsGT 1 Treatment-Naïve (ION-1)

14

Error bars represent 95% confidence intervals.Mangia, A. et al. EASL 2014, Abstract #O164

Results: SVR12GT 1 Treatment-Naïve (ION-1)

0

20

40

60

80

10099 97 98 99

211/217

12 Weeks 24 Weeks

LDV/SOF + RBV

211/214 212/217

SV

R12

(%

)

215/217

LDV/SOF + RBVLDV/SOF LDV/SOF

15

Abstract #O109

All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients:

The Phase 3 ION-2 Study

Nezam Afdhal1, Rajender K. Reddy2, Paul Pockros3, Adrian M. Di Bisceglie4, Sanjeev Arora5,Jenny C. Yang6, Hadas Dvory-Sobol6, Yanni Zhu6, Phil S. Pang6, William T. Symonds6,

John G. McHutchison6, Mark Sukowski7, Paul Kwo8

1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2University of Pennsylvania, Philadelphia, PA, USA; 3Scripps Clinic, La Jolla, CA; 4St Louis University, Saint Louis, MO, USA; 5University of New Mexico, Albuquerque, NM; 6Gilead Sciences, Inc., Foster City, CA; 7Johns Hopkins Medical Center, Baltimore, MD,

USA; 8Indiana University School of Medicine, Indianapolis, IN, USA

16

• GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor

• Broad inclusion criteria– Targeted 20% enrollment of patients with cirrhosis– No upper age or BMI limit– Platelet count ≥50,000/mm3, no neutrophil minimum

• 440 patients randomized 1:1:1:1 across four arms• Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response

Wk 0 Wk 12 Wk 36Wk 24

LDV/SOF SVR12

LDV/SOF + RBV

LDV/SOF

LDV/SOF + RBV

SVR12

SVR12

SVR12

Afdhal, N. et al. EASL 2014, Abstract #O109

Study DesignGT 1 Treatment-Experienced (ION-2)

17

• Arms were balanced with respect to demographics and baseline characteristics

12 Weeks 24 Weeks

LDV/SOFn=109

LDV/SOF+RBVn=111

LDV/SOFn=109

LDV/SOF+RBVn=111

Mean age, y (range) 56 (24–67) 57 (27–75) 56 (25–68) 55 (28–70)

Male, n (%) 74 (68) 71 (64) 74 (68) 68 (61)

Black, n (%) 24 (22) 16 (14) 17 (16) 20 (18)

Hispanic, n (%) 7 (6) 12 (11) 11 (10) 11 (10)

Mean BMI, kg/m2 (range) 29 (19–47) 28 (19–45) 28 (19–41) 28 (19–50)

IL28B CC, n (%) 10 (9) 11 (10) 16 (15) 18 (16)

GT 1a, n (%) 86 (79) 88 (79) 85 (78) 88 (79)

Mean HCV RNA,log10 IU/mL (range) 6.5 (5.0–7.5) 6.4 (4.6–7.3) 6.4 (4.7–7.4) 6.5 (3.1–7.4)

HCV RNA ≥800,000 IU/mL 103 (95) 98 (88) 93 (85) 96 (87)

Prior non-responders, n (%)

49 (45) 46 (41) 49 (45) 51 (46)

Prior protease inhibitor failures, n (%)

66 (61) 64 (58) 50 (46) 51 (46)

Cirrhosis, n (%) 22 (20) 22 (20) 22 (20) 22 (20)

Afdhal, N. et al. EASL 2014, Abstract #O109

Results: DemographicsGT 1 Treatment-Experienced (ION-2)

18

0

20

40

60

80

10094 96 99 99

107/111

12 Weeks 24 Weeks

LDV/SOF + RBV

102/109 108/109

SV

R12

(%

)

110/111

LDV/SOF + RBVLDV/SOF LDV/SOF

Error bars represent 95% confidence intervals.Afdhal, N. et al. EASL 2014, Abstract #O109

Results: SVR12GT 1 Treatment-Experienced (ION-2)

19


SVR12: PEG/RBV vs PI + PEG/RBV Failures GT 1 Treatment-Experienced (ION-2)

0

20

40

60

80

100 93 96 100 9894 97 98 100

Failed PEG/RBV Failed Protease Inhibitor

SV

R12

(%

)

40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF

20

0

20

40

60

80

10095 100 99 9986 82

100 100

Absence of Cirrhosis Cirrhosis

SV

R12

(%

)

83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF


SVR12: Absence of Cirrhosis vs CirrhosisGT 1 Treatment-Experienced (ION-2)

21

Abstract #O60

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

ABT-333, And Ribavirin In 631 Treatment-Naïve Adults With Hepatitis C Virus Genotype 1

J.J. Feld1, K.V. Kowdley2, E. Coakley3, S. Sigal4, D. Nelson5, D. Crawford6,7, O. Weiland8, H. Aguilar9,J. Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3

1Toronto Western Hospital Liver Centre, Toronto, ON, Canada, 2Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, 3AbbVie Inc., North Chicago, IL, 4NYU Langone Medical Center, New York, NY, 5University of Florida College of Medicine, Gainesville, FL, United States, 6Gallipoli Medical Research

Foundation, 7The University of Queensland, Brisbane, QLD, Australia, 8Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden, 9Louisiana Research Center, LLC, Shreveport, LA,

United States

22

• 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=473)

Placebo(n=158) 3D + RBV

Double-BlindTreatment Period

Open-LabelTreatment Period

Primary Analysis: SVR12

48-WeekFollow-Up

48-WeekFollow-Up

Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Placebo-Controlled Design (N=631)

23

SV

R12

, %

Pat

ien

ts

All Patients

96.2% 95.3% 98.0%

455/473 307/322 148/151

GT1a GT1b


SAPPHIRE-I Results: ITT SVR12 Rates (Superiority to Calculated Placebo Rate)

24

Event, n/N (%)3D + RBV(N=473)

SVR12 455/473 (96.2)

Non-SVR12 18/473 (3.8)

Virologic failure

Breakthrough 1/473 (0.2)

Relapse 7/463 (1.5)

Prematurely discontinued study drug* 7/473 (1.5)

Lost to follow-up after completion of treatment 3/473 (0.6)

Breakthrough and relapse rates of 0.2% and 1.5%, respectively

*Patients (n=7) who prematurely discontinued without breakthrough; 2 due to adverse events, 5 withdrew consent/ lost to follow-up.Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Reasons for Non-SVR12

25

SV

R12

, %

Pat

ien

ts

Male Female Black Non-Black

<30 >30 F0-F1

F2 F3 <800K >800K Yes No

271 202 28 445 402 71 363 70 40 104 369 31 442

Gender Race RBVModification

BMI(kg/m2)

FibrosisStage

BaselineHCV RNA

(IU/mL)

95.2 97.5 96.4 96.2 97.0 91.5 97.0 94.3 92.5 98.1 95.7 93.5 96.4


SAPPHIRE-I: ITT SVR12 Rates in Subpopulations

26

Event, n (%)3D + RBV(N=473)

Placebo(N=158) P Value

Any AE 414 (87.5) 116 (73.4) <0.05

Fatigue 164 (34.7) 45 (28.5) NS

Headache 156 (33.0) 42 (26.6) NS

Nausea 112 (23.7) 21 (13.3) <0.05

Pruritus 80 (16.9) 6 (3.8) <0.05

Insomnia 66 (14.0) 12 (7.6) <0.05

Diarrhea 65 (13.7) 11 (7.0) <0.05

Asthenia 57 (12.1) 6 (3.8) <0.05

Rash 51 (10.8) 9 (5.7) NS

AEs were generally mild.Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Adverse Events Occurring in >10% of Patients in Either Group

27

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, 6H_pital 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

28



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

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

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

29

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)

SAPPHIRE-II: Baseline Patient Characteristics


30

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


31

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

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

32

• No patient had breakthrough and 2.4% of patients had a relapse

AllPatients(N=297)

PriorRelapsers

(N=86)

Prior PartialResponders

(N=65)

Prior NullResponders

(N=146)

SVR12, n/N (%) 286/297 (96.3)

82/86 (95.3)

65/65 (100)

139/146 (95.2)

Virologic failure, n

Breakthrough 0 0 0 0

Relapse 7 1 0 6

Prematurely discontinued study drug,* n 4 3 0 1

*Patients (n=4) who prematurely discontinued without breakthrough; 3 due to adverse events, 1 withdrew consent during week 11.Zeuzem, S. et al. EASL 2014, Abstract #O1

SAPPHIRE-II: SVR12 and Reasons forNon-Response in Patients Receiving 3D + RBV

33

Event, n (%)3D + RBV(N=297)

Placebo(N=97) P Value

Any AE 271 (91.2) 80 (82.5) <0.05

Headache 108 (36.4) 34 (35.1) NS

Fatigue 99 (33.3) 22 (22.7) NS

Nausea 60 (20.2) 17 (17.5) NS

Asthenia 47 (15.8) 11 (11.3) NS

Insomnia 42 (14.1) 7 (7.2) NS

Pruritus 41 (13.8) 5 (5.2) <0.05

Diarrhea 39 (13.1) 12 (12.4) NS

Dyspnea 37 (12.5) 10 (10.3) NS

Cough 32 (10.8) 5 (5.2) NS

Myalgia 23 (7.7) 10 (10.3) NS

AEs were generally mild.Zeuzem, S. et al. EASL 2014, Abstract #O1

SAPPHIRE-II: Adverse Events Occurring in >10% of Patients in Either Group

34

Event, n/N (%)3D + RBV(N=297)

Placebo(N=97)

ALT >5X ULN 5/296 (1.7) 3/96 (3.1)

AST >5X ULN 3/296 (1.0) 1/96 (1.0)

Alkaline phosphatase >5X ULN 0 0

Total bilirubin >3X ULN 7/296 (2.4) 0


SAPPHIRE-II: Laboratory Abnormalities

• No patient met Hy’s Law criteria• Elevations in total bilirubin were mainly transient and

predominantly indirect bilirubin• Bilirubin elevations were not concomitant with ALT or AST

elevations • Total bilirubin increases normalized by post-treatment week 4

35

Abstract #O163

TURQUOISE-II: SVR12 Rates 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

(3D+RBV)

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

36



Day 0 Week 24Week 12

SVR12

SVR12

3D + RBV(N=208)

3D + RBV(N=172)

All patients to be followed through 48 weeks post-treatment

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

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

37Poordad, F. et al. EASL 2014, Abstract #O163

TURQUOISE-II: Eligibility Criteria

• Treatment-naïve and pegIFN/RBV-experienced genotype 1 HCV infected patients, with no prior therapy with direct acting antiviral agents

• Compensated (Child-Pugh A) cirrhosis at screening• Cirrhosis documented using liver biopsy, or FibroScan

(≥14.6 kPa) within 6 months of or during screening• Platelet count ≥60,000 cells/mL• Serum albumin ≥2.8 g/dL• Total bilirubin <3 mg/dL• INR ≤2.3• AFP ≤100 ng/mL• Patients with radiographic ascites and patients with varices

were allowed

38

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


TURQUOISE-II: Demographics and Patient Characteristics

39

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


0

20

40

60

80

100S

VR

12,

% P

atie

nts

12 Weeks3D + RBV

91.8

191/208

95.9

165/172

24 Weeks3D + RBV

P=0.089

40

0

20

40

60

80

10092.2

12-week arm

24-week arm

92.9

Naïve Prior RelapseResponse

3D + RBV

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 1aPoordad, F. et al. EASL 2014, Abstract #O163

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

41

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, 13H_pital 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, 18H_pital 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

42

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

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

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

42

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

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

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-naive

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

43Manns, M. et al. EASL 2014, Abstract #O166

Patient Baseline Characteristics

Parameter

Treatment-naiveDCV + ASV(N = 205)

Treatment-naivePlacebo(N = 102)

Nonrespondera

(N = 205)

Ineligible/intolerantb

(N = 235)

Age, median years 55 54 58 60

Male, n (%) 101 (49) 54 (53) 111 (54) 98 (42)

Race, n (%)

White 135 (66) 59 (58) 148 (72) 169 (72)

Black 14 (7) 8 (8) 10 (5) 10 (4)

Asian 52 (25) 33 (32) 45 (22) 56 (24)

HCV RNA, n (%)

< 800,000 log10 IU/mL 53 (26) 26 (25) 27 (13) 48 (20)

≥ 800,000 log10 IU/mL 152 (74) 76 (75) 178 (87) 187 (80)

Cirrhosis, n (%) 33 (16) 16 (16) 63 (31) 111 (47)

IL28B genotype, n (%)

CC 76 (37) N/A 29 (14) 82 (35)

Non-CC 129 (63) N/A 173 (84) 143 (61)a Includes 119 (58%) null responders, 84 (41%) partial responders, and 2 (1%) relapsers.b Includes 71 (30%) patients with depression, 87 (37%) with anemia/neutropenia, and 77 (33%) with compensated advanced fibrosis/cirrhosis with thrombocytopenia (6 with advanced fibrosis [F3], 70 with cirrhosis [F4], and 1 not reported).

44

0

20

40

60

80

100 9082 82

Treatment-naive

Nonresponders Ineligible/intolerant

SV

R12

(%

of

pat

ien

ts)a,

b

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

Virologic Response: SVR12

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

182/203 168/205 192/235

Lisa Pedicone

this one and the next also in feld deck. I added the x/y after the presentation. Please swap any slides that are the saem as the feld deck with those from feld.

45

0

20

40

60

80

100 9082 81 80

91

73

SV

R12

(%

of

pat

ien

ts)

Nonresponder Ineligible/intolerantTreatment-naive

Null Partial Depression Anemia/neutropeniaa

Advancedfibrosis/cirrhosisw/ thrombocytopeniab

a Anemia: screening hemoglobin 8.5 to < 12 (female) or < 13 (male) g/dL and/or history of anemia on pegIFN/RBV;

neutropenia: screening absolute neutrophils 0.5 to < 1.5 x 109 cells/L and/or history of neutropenia on pegIFN/RBVb Screening platelets 50 to < 90 x 109 cells/L and/or history of thrombocytopenia on pegIFN/RBVManns, M. et al. EASL 2014, Abstract #O166

Virologic Response by Patient Subgroup

182/203 98/119 68/84 57/71 79/87 56/77

46

Patients Without SVR12

46

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

Patients, n (%)

Treatment-naive

(N = 203)Nonresponder

(N = 205)

Ineligible/intolerant(N = 235)

All 21 (10) 37 (18) 43 (18)

On-treatment failures

Virologic breakthrough 9 (4) 26 (13) 20 (9)

Futility 0 0 1 (0.4)

Detectable or missing RNA at end of treatment 4 (2) 3 (1) 8 (3)

Posttreatment failures

Relapsea 5 (3) 7 (4) 12 (6)

Missing RNA at posttreatment Week 12a 3 (2) 1 (1) 2 (1)

a Percentages based on number of patients with undetectable HCV RNA at end of treatment (treatment-naive, n = 189; nonresponder, n = 174; ineligible/intolerant, n = 204).

47

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

48Lawitz, E. et al. EASL 2014, Abstract #O61

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

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

Treatment-naive Non-cirrhotic

8-12 weeks ± RBV(n = 94)

Treatment-naive 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)

49

Efficacy of MK-5172 + MK-8742 ± RBV in 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

ati

en

ts H

CV

RN

A <

25

IU

/mL

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

Lawitz, E. et al. EASL 2014, Abstract #O61

50

0

10

20

30

40

50

60

70

80

90

100 94 94 94100 100

9197 100 100

94 97 9712 wk, + RBV (n=32)


18 wk, + RBV (n=33)


% P

ati

en

ts H

CV

RN

A <

25

IU

/mL

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

Lawitz, E. et al. EASL 2014, Abstract #O61

1 stefan zeuzem, md frankfurt, germany this activity is supported by an independent medical...

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