1 catherine stedman, md christchurch, new zealand this activity is supported by an independent...

1

Best of HCV from EASL

Catherine Stedman, MDChristchurch, New Zealand

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

2

Abstract #O55

Successful Retreatment of HCV Genotype-1 Infected Patients Who Failed Prior Therapy with Peg-interferon + Ribavirin Plus

1 or 2 Other Direct-Acting Antiviral Agents with Sofosbuvir

Stanislas Pol1, Mark Sulkowski2, Tarek Hassanein3, Ed Gane4, Liyun Ni5, Hongmei Mo5, Bittoo Kanwar5, Diana Brainard5, GM Subramanian5, William T. Symonds5,

John G. McHutchison5, Michael Bennett6, Ira M. Jacobson7

1Universite Paris Decartes, Hopital Cochin, Paris, France; 2John Hopkins University, Baltimore, MD, USA; 3Southern California Liver Center, Coronado, CA, USA; 4Aukland City Hospital, Auckland, NZ; 5Gilead

Sciences, Inc., Foster City, CA, USA; 6Medical Associates Research Group, San Diego, CA, USA; 7Weill Cornell Medical College, New York, NY, USA

3

Study Methods and Design

• All patients were previously treated with PEG+RBV and an investigational protease inhibitor (GS-9451 or GS-9256) +/- one or two additional DAA

– Tegobuvir (NS5b non-nucleoside polymerase inhibitor)

– Ledipasvir (NS5a inhibitor)

• No patients had documented cirrhosis as per the prior protocols

SVR 12SOF + PEG/RBV

Wk 0 Wk 12 Wk 24

Pol, S. et al. EASL 2014, Abstract #O55

4

Results: Baseline Demographics

12 weeks SOF + PEG/RBV

n=80

Mean age, y (range) 55 (21–72)

Male, n (%) 60 (75)

Black, n (%) 11 (14)

Mean BMI, kg/m2 (range) 28 (21–43)

IL28B CC, n (%) 13 (16)

Mean ALT, U/L (range) 74 (24-298)

GT 1a, n (%) 68 (85)

Mean baseline HCV RNA, log10 IU/mL (range) 6.6 (5.0–7.3)

Mean duration of prior therapy, weeks (range) 25 (1–60)

Courses of prior therapy, n (%)

1 44 (55)

≥2 36 (45)

Prior DAA Exposure, n (%)

1 DAA 15 (19)

2 DAA 41 (51)

3 DAA 24 (30)

Patients with ≥1 resistance associated variant (RAV), n(%) 72 (90)

Prior response, n (%)

Relapse 48 (48)

On-treatment failure 36 (45)


5

Results: Viral Response and SVR12

Week 4 End of Treatment SVR120

20

40

60

80

10099 100

74

HC

V R

NA

< L

LO

Q (

%)

66/67 67/67 37/50


6

Conclusions

• Three quarters (74%) of DAAs-experienced patients achieved an SVR with 12 weeks of SOF + PEG/RBV therapy despite multiple resistance variants and prior courses of therapy

• The presence of baseline RAVs against any or all 3 non structural proteins (NS3, NS5a, NS5b) did not impact overall SVR

• The 12-week SOF + PEG/RBV regimen was safe and well tolerated

• Sofosbuvir-containing regimens are effective in these patients with no other currently approved alternatives


7

Abstract #O8

Successful Retreatment With Sofosbuvir-containing Regimens for HCV Genotype 2 or 3 Infected Patients who Failed Prior

Sofosbuvir Plus Ribavirin Therapy

Rafael Esteban1, Lisa Nyberg2, Jay Lalezari3, Liyun Ni4, Brian Doehle4, Bittoo Kanwar4, Diana Brainard4, GM Subramanian4, William T. Symonds4, John G. McHutchison4,

Maribel Rodriquez-Torres5, Stefan Zeuzem6

1Vall d’Hebron Hospital, Barcelona, Spain; 2Kaiser Permanente, San Diego, CA, USA; 3Quest Clinical Research, San Francisco, CA, USA; 4Gilead Sciences, Inc., Foster City, CA, USA;

5Fundacion de Investigacion, San Juan, Puerto Rico; 6JW Goethe University Hospital, Frankfurt, Germany

8

Methods

• Open-label study offered to all GT 2 or 3 treatment failures from FISSION, POSITRON and FUSION

• Patients offered 2 possible treatment options

– Choice based on patient’s eligibility for IFN and patient/investigator recommendation

• Included patients with compensated cirrhosis

SVR 12

SOF + PEG/RBV SVR 12

SOF + RBV

Wk 0 Wk 12 Wk 24 Wk 36

Esteban, R. et al. EASL 2014, Abstract #O8

9

Results: Baseline Characteristics12 weeks

SOF + PEG/RBVn=34

24 weeks SOF + RBV

n=73

Mean age, y (range) 53 (31–70) 53 (38-63)

Male, n (%) 26 (77) 63 (86)

Black, n (%) 1 (1%) 0

Mean BMI, kg/m2 (range) 29 (22–39) 28 (20-41)

Cirrhosis* n (%) 14 (41) 25 (34)

IL28B CC, n (%) 11 (32) 27 (37)

Mean ALT, U/L (range) 96 (14-325) 89 (18-310)

Genotype, n (%)

2 6 (18) 5 (7)

3 28 (82) 68 (93)

Mean baseline HCV RNA, log10 IU/mL (range) 6.3 (4.8-7.8) 6.6 (4.4–7.6)

*Cirrhosis status determined in parent protocol.


10

Results: On Treatment Viral Response and SVR 12

Week 4 End of Treatment SVR 12 0

20

40

60

80

100100 100 92100 100

63

12 weeks SOF+PEG/RBV 24 weeks SOF+RBV

Pat

ien

ts w

ith

< L

LO

Q (

%)

28/28 50/50 24/26 25/4028/28 50/50

• Relapse accounted for all virologic failures

Error bars represent 95% confidence intervals.


11

Results: GT 3 SVR12 by Cirrhosis Status

12 weeks SOF + PEG/RBV 24 weeks SOF+RBV0

20

40

60

80

100 93

74

88

47

No Cirrhosis Cirrhosis

Pat

ien

ts w

ith

< L

LO

Q (

%)

13/14 7/8 17/23 7/15


12

Conclusions

• Retreatment with an extended duration of SOF + RBV to 24 weeks or the addition of IFN to a 12 week regimen resulted in high SVR rates in GT 2 and GT 3 patients who previously failed SOF+RBV-containing regimens

• The 12-week regimen containing IFN had higher overall rates of SVR and was more effective in patients with cirrhosis

• The 24-week IFN-free regimen was safe and well tolerated and offers a retreatment option for those ineligible to receive IFN


13

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

14

• 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)

15

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

(%

)

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%

16

*Excluding patients who discontinued for non-virologic reasons

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

17


GT 1a without Q80K

100 100

9388

95100 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



18


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



19


COSMOS Cohort 2: SVR12 by Treatment History – 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

20

COSMOS Cohort 2: 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)

GT, genotype; ITT, Intent-to-treat; QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentLawitz, E. et al. EASL 2014, Abstract #O165

21

Abstract #O109

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,3

Graham 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

22

Study DesignGT 1 Treatment-Naïve (ION-1)

• 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

Lawitz, E. et al. EASL 2014, Abstract #O109

23

• 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)

Mangia, A. et al. EASL 2014, Abstract #O109

24

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


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


25

ConclusionsGT 1 Treatment-Naïve (ION-1)

• LDV/SOF for 12 weeks achieved SVR12 rate of 99% in treatment-naive GT 1 patients

– Adding RBV and/or extending LDV/SOF treatment duration to 24 weeks did not increase SVR12 rates

– Cirrhotic patients achieved SVR12 rates of 94 - 100% with 12-24 weeks of treatment with LDV/SOF with or without RBV

• LDV/SOF with or without RBV was safe and well tolerated

– Addition of RBV contributed to higher incidence of AEs and laboratory abnormalities

• A single tablet regimen with the fixed-dose combination LDV/SOF for 12 weeks achieved SVR in most GT 1 previously un-treated patients


26

Abstract #O164

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

27

• 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 #O164

Study DesignGT 1 Treatment-Experienced (ION-2)

28

• 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)


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

29

0

20

40

60

80

100 94 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


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


30

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



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

31

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)

32

Conclusions GT 1 Treatment-Experienced (ION-2)

• Single tablet fixed dose combination of LDV/SOF with or without RBV in treatment-experienced GT 1 patients resulted in an SVR of 94 -99%

• Baseline NS5a or NS3/4 mutations had no effect on SVR

• RBV did not enhance SVR rates, alter viral kinetics or prevent relapse

• The majority of subjects who relapsed had cirrhosis

• LDV/SOF ± RBV was safe and well tolerated

– Addition of RBV contributed to higher incidence of AEs and laboratory abnormalities

Afdhal N, et al. NEJM In PressAfdhal, N. et al. EASL 2014, Abstract #O164

33

Abstract #O56

Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in

Treatment-Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study

Kris V. Kowdley1, Stuart C. Gordon 2, K. Rajender Reddy3, Lorenzo Rossaro4, David E. Bernstein5,Di An6, Evguenia S. Svarovskaia6, Robert H. Hyland6, Phillip S. Pang6,

William T. Symonds6, John G. McHutchison6, Andrew J. Muir7, Paul J. Pockros8, David C. Pound9, Michael W. Fried10

1Virginia Mason Medical Center, Seattle, WA, USA; 2Henry Ford Health System, Detroit, MI, USA; 3Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4University of

California Davis Medical Center, Sacramento, CA, USA; 5North Shore University Hospital, Manhasset, NY, USA; 6Gilead Sciences, Inc., Foster City, CA; 7Division of Gastroenterology and Duke Clinical Research

Institute, Duke University School of Medicine, Durham, NC, USA; 8Scripps Clinic, La Jolla, CA; 9Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, USA; 10University of North Carolina at Chapel Hill,

Chapel Hill, NC, USA

34

• GT 1 treatment-naïve patients without cirrhosis• Broad inclusion criteria

– No upper age or BMI limit

– Opiate substitution therapy allowed

• 647 patients randomized 1:1:1 across three arms• Stratified by HCV subtype (1a or 1b)

LDV/SOF

LDV/SOF

LDV/SOF + RBV

Wk 0 Wk 8 Wk 12 Wk 24Wk 20

SVR12

SVR12

SVR12

Kowdley, K. et al. EASL 2014, Abstract #O56

Study DesignGT 1 Treatment-Naïve (ION-3)

35

0

20

40

60

80

100

p=0.70 p=0.30

206/216

8 Weeks 12 Weeks

LDV/SOFLDV/SOF LDV/SOF + RBV

201/216202/215 206/216

SV

R12

(%

)p=0.52

Kowdley, K. et al. EASL 2014, Abstract #O56

Results: Non-Inferiority ComparisonGT 1 Treatment-Naïve (ION-3)


36

Kowdley K, et al. NEJM In PressKowdley, K. et al. EASL 2014, Abstract #O56

ConclusionsGT 1 Treatment-Naïve (ION-3)

• LDV/SOF ± RBV for 8 or 12 weeks results in highSVR12 rates

• No difference in efficacy among the groups was observed

• Host and viral factors traditionally associated with lower SVR rates did not affect SVR12 rates

• LDV/SOF ± RBV was safe and well tolerated

– RBV contributed to a higher incidence of AEs and laboratory abnormalities

• An 8 week LDV/SOF treatment regimen is a safe and effective treatment for treatment-naïve non-cirrhotic patients with HCV GT 1 infection

37

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

38

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

39

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


40

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

41

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

42Gane, 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

43

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

44

• 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)

45

HCV genotype and subtype were assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0.

3D + RBV(N=473)

Placebo(N=158)

Male, n (%) 271 (57.3) 73 (46.2)

Race, n (%)

White 428 (90.5) 144 (91.1)

Black 26 (5.5) 8 (5.1)

Hispanic/Latino ethnicity, n (%) 27 (5.7) 5 (3.2)

Median age, years (range) 52.0 (18.0-70.0) 52.0 (21.0-70.0)

Median BMI, kg/m2 (range) 25.2 (18.0-38.4) 25.5 (18.5-39.4)

Fibrosis stage, n (%)

F0-F1 363 (76.7) 116 (73.4)

F2 70 (14.8) 27 (17.1)

F3 40 (8.5) 15 (9.5)

IL28B non-CC genotype, n (%) 329 (69.6) 108 (68.4)

HCV subtype, n (%)

1a 322 (68.1) 105 (66.5)

1b 151 (31.9) 53 (33.5)

Median HCV RNA, log10 IU/mL (range) 6.51 (3.58-7.60) 6.64 (3.71-7.51)


SAPPHIRE-I: Baseline Patient Characteristics

46

SV

R1

2, %

Pa

tien

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)


47Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Conclusions

The ITT SVR12 rate was 96.2% (455/473) for treatment-naïve GT1-infected patients receiving 12 weeks of co-formulated ABT-450/r/ombitasvir + dasabuvir + RBV

SVR12 rates (ITT) were high regardless of HCV subtype

The rate of virologic failure was low:

– 0.2% breakthrough rate

– 1.5% relapse rate

The regimen was generally well-tolerated, with a low rate of study drug discontinuation due to AE(s) (0.6%)

48

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

49

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

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

50

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

51Zeuzem, 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

52Zeuzem, 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

53

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

54

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

55

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



Day 0 Week 24Week 12

SVR12

SVR12

3D + RBV(N=208)

3D + RBV(N=172)

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

All patients to be followed through 48 weeks post-treatment

56

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


57

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


58

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


59

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

60

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

61

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-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

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

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

62

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).


63

0

20

40

60

80

100 9082 82

Virologic Response: SVR12

Treatment-naive

Nonresponders Ineligible/intolerant

SV

R12

(%

of

pat

ien

ts)a,

b

• SVR12 rates documented on or after posttreatment Week 12– Treatment-naive: 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

64

Virologic Response by Patient Subgroup

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

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

65

Patients Without SVR12

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).


66

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

91% in treatment-naive, 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


1 catherine stedman, md christchurch, new zealand this activity is supported by an independent...

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