best of hcv from aasld 2013

1

Best of HCVFrom AASLD 2013

Jointly sponsored by the Duke University School of Medicine and the Chronic Liver Disease Foundation

Michael P. Manns, MDHannover, Germany

2

Disclosures M. P. Manns, MD• Advisory Board Membership:

Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Janssen, Merck, Novartis, Roche

3

GT 1 Interferon-Free

4

Abstract #LB-3

SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic

HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study

Ira M. Jacobson1, Reem H. Ghalib2, Maribel Rodriguez-Torres3, Zobair M. Younossi4, Ana Corregidor5, Mark S. Sulkowski6, Edwin DeJesus7, Brian Pearlman8, Mordechai Rabinovitz9, Norman Gitlin10, Joseph K. Lim11,

Paul J. Pockros12, Bart Fevery13, Tom Lambrecht14, Sivi Ouwerkerk-Mahadevan13, Katleen Callewaert13, William T. Symonds15, Gaston Picchio16, Karen Lindsay16, Maria Beumont-Mauviel13, Eric Lawitz17

1. Weill Cornell Medical College, New York, NY, United States. 2. Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, United States. 3. Fundación de Investigación, San Juan, Puerto Rico, United States. 4. Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States. 5. Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, United States. 6. Johns Hopkins University School of Medicine, Baltimore, MD, United States. 7. Orlando Immunology Center, Orlando, FL, United States. 8. Atlanta Medical Center, Atlanta, GA, United States.

9. University of Pittsburgh Medical Center, Pittsburgh, PA, United States. 10. Atlanta Gastroenterology Association, Atlanta, GA, United States. 11. Yale School of Medicine, New Haven, CT, United States. 12. Scripps Clinic, La Jolla, CA, United States. 13. Janssen Research & Development, Beerse, Belgium. 14. Novellas Healthcare, Zellik, Belgium. 15. Gilead Sciences Inc, Foster City, CA, United States. 16. Janssen Research & Development LLC, Titusville, NJ, United States. 17. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States.

5

Background

• Simeprevir (TMC435) is an investigational, one pill, once-daily, potent oral HCV NS3/4A protease inhibitor recently approved in Japan and currently under regulatory review in North America and Europe

• Sofosbuvir (GS-7977) is an HCV nucleotide NS5B polymerase inhibitor also currently under regulatory review

• COSMOS is a Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin

• Interim analysisJacobson IM, et al. Abstract #LB-3, AASLD 2013

6

COSMOS: Study design

• Cohort 1: Prior null responders (METAVIR F0-F2)– Final SVR12 for all arms

• Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4)– Interim SVR4 for Arms 3 and 4

SMV + SOF + RBV Post-treatment follow-up

0 4 12 24 36 48

Arm 1

Week

SMV + SOF

SMV + SOF + RBV

SMV + SOF

Post-treatment follow-up



Arm 2

Arm 3

Arm 4

Enrollment ratio 2:1:2:1

N=14

N=24

N=14

N=27

Jacobson IM, et al. Abstract #LB-3, AASLD 2013

7

SMV/ SOF12 Wks

SMV/ SOF/RBV12 Wks

0102030405060708090

100

92 96

7.83.7

24 week treatment

13/14 26/27

SMV/SOF12 wks

SMV/SOF/RBV12 wks

SVR12 (SMV/SOF)

SVR12 (SMV/SOF/RBV)

1/271/14

0102030405060708090

100

93.3 79

16.7

4.2

14/15 19/24

SMV/SOF24 wks

SMV/SOF/RBV 24 wks

Pat

ien

ts (

%)

1/24

4/241/15

Non-virologic failure

Relapse

Cohort 1: Null responders (F0-2)12 week treatment


6.7

8

Total Naives Nulls0

102030405060708090

100100 100 10096.3 100

93.3

Pat

ien

ts (

%)

1/27

SVR4 (SMV/SOF)

SVR4 (SMV/SOF/RBV)

12 week treatment

7/7 12/12 7/7 14/15

1/15

Relapse

26/2714/14

Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4


9

Most Common AEs: Cohorts 1 and 2 Combined24 weeks 12 weeks

Patients, n (%)SMV + SOF + RBV (n=54)

SMV + SOF (n=31)

SMV + SOF + RBV (n=54)

SMV + SOF (n=28)

Fatigue 20 (37.0) 10 (32.3) 13 (24.1) 7 (25.0)

Headache 11 (20.4) 7 (22.6) 9 (16.7) 6 (21.4)

Nausea 6 (11.1) 4 (12.9) 8 (14.8) 6 (21.4)

Insomnia 9 (16.7) 2 (6.5) 5 (9.3) 4 (14.3)

Rash 7 (13.0) 3 (9.7) 8 (14.8) 1 (3.6)

Pruritus 9 (16.7) 1 (3.2) 5 (9.3) 3 (10.7)

Photosensitivity/sunburna 2 (3.7) 1 (3.2) 3 (5.6) 2 (7.1)

Anemia 11 (20.4) 1 (3.2) 6 (11.1) 0

aNo sun-protective measures were in place for this trialRBV, ribavirin; SMV, simeprevir; SOF, sofosbuvirJacobson IM, et al. Abstract #LB-3, AASLD 2013

10

• Treatment with SMV + SOF ± RBV results in:– High SVR12 rates in HCV GT 1 null responder patients– High SVR4 rates in naïve and null-responder patients with METAVIR

F3-F4

• Addition of RBV to SMV + SOF may not be needed to achieve high rates of SVR in this patient population

• 12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment

• SMV + SOF ± RBV was generally well tolerated

Conclusion


11

Abstract #211

All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder

Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial

Kazuaki Chayama1, Yoshiyuki Suzuki2, Kenji Ikeda2, Joji Toyota3, Yoshiyasu Karino3, Yoshiiku Kawakami1, Akio Ido4, Kazuhide Yamamoto5, Koichi Takaguchi6, Namiki Izumi7, Kazuhiko Koike8, Tetsuo Takehara9, Norifumi Kawada10, Michio Sata11, Hidetaka

Miyagoshi12, Timothy Eley13, Fiona McPhee13, Wenhua Hu13, Hiroki Ishikawa12, Eric A. Hughes13, Hiromitsu Kumada2

1. Hiroshima University, Hiroshima, Japan. 2. Toranomon Hospital, Tokyo, Japan. 3. Sapporo-Kousei General Hospital, Sapporo, Japan. 4. Kagoshima University, Kagoshima, Japan. 5. Okayama University, Okayama, Japan. 6. Kagawa Prefectural Hospital, Kagawa, Japan.7. Musashino Red Cross Hospital, Tokyo, Japan.

8. University of Tokyo, Tokyo, Japan. 9. Osaka University, Osaka, Japan. 10. Osaka City University, Osaka, Japan. 11. Kurume University, Fukuoka, Japan. 12. Bristol-Myers KK, Tokyo, Japan. 13. Bristol-Myers Squibb, Princeton, NJ, United States.

12

HCV RNA < LLOQ, n (%) Ineligible naïve/Intolerant

(IN/I) Patients n = 135a

Nonresponder (NR) Patients n = 87b

Total N = 222

RVR, Week 4 114 (84.4) 53 (60.9) 167 (75.2)

cEVR, Week 12 125 (92.6) 77 (88.5) 202 (91.0)

SVR4 126 (93.3) 71 (81.6) 197 (88.7)

SVR12 120 (88.9) 70 (80.5) 190 (85.6)

SVR24 118 (87.4) 70 (80.5) 188 (84.7)

Virologic Response

aIneligible naïve: n=100; Intolerant: n=35 bNull responders: n=48; Partial responders: n=36; Undetermined: n=3

Chayama K, et al. Abstract #211, AASLD 2013

13

Abstract #75

Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and

Prior Null Responders

Eric Lawitz1, Christophe Hezode2, Peter Varunok3, Paul J. Thuluvath4, Tolga Baykal5, Mudra Kapoor5, Sandra S. Lovell5, Tianli Wang5, Tami Pilot-Matias5, Regis A. Vilchez5, Barry Bernstein5

1. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States.

2. Assistance Publique Hopitaux de Paris, Paris, France. 3. Premier Medical Group of the Hudson Valley, PC, Poughkeepsie, NY, United States.

4. The Institute for Digestive Health and Liver Disease at Mercy, Baltimore, MD, United States. 5. AbbVie Inc., North Chicago, IL, United States.

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Background and Aims

• ABT-450 is an HCV protease inhibitor

(dosed with ritonavir 100 mg, ABT-450/r)

• ABT-267 is an NS5A inhibitor

• Both compounds have shown potent antiviral

activity in vitro against HCV genotypes (GT)

1-4 and 6.

Lawitz E, et al. Abstract #75, AASLD 2013

15

PEARL-I Study Design

Substudy 1:PatientsWithoutCirrhosis

Substudy 2:Patients With Compensated Cirrhosis

Group 1 40

Group 2 40

Group 3 40

Group 4 40

Group 5 40

Group 6 40

Group 7 40

Group 8 40

PlannedN

HCV Genotype/RegimenTreatment Experience Week 12 Week 24

GT4 ABT-450/r + ABT-267Treatment-naïve

GT1b ABT-450/r + ABT-267Treatment-naïve

GT1b ABT-450/r + ABT-267Null Responders

GT4 ABT-450/r + ABT-267 + rbvTreatment-naïve

GT4 ABT-450/r + ABT-267Partial/Null Responders & Relapsers

GT4 ABT-450/r + ABT-267 + rbvPartial/Null Responders & Relapsers

GT1b ABT-450/r + ABT-267Treatment-naïveGT1b ABT-450/r + ABT-267Partial/Null Responders & Relapsers

BL


16

Efficacy: Treatment-Naïve Patients, ITT

Week 4 Week 12 (EOTR)

SVR4 SVR12

0

20

40

60

80

100P

erc

en

tag

e o

f Pa

tien

ts (

%) 100 97.6

42/42 41/42 41/42 40/42

97.6 95.2


17

39/40 39/40 37/40

97.597.5 92.5 90.0

36/40

Efficacy: Prior Null Responders, ITT

Week 4 Week 12(EOTR)

SVR4 SVR12

0

20

40

60

80

100P

erc

en

tag

e o

f Pa

tien

ts (

%)


18

Treatment-Emergent Adverse Events (AEs) Occurring in >10% of Patients in Either Group

Event, n (%)GT1b-infected

Treatment-naïve Patients(N=42)

GT1b-infectedPrior Null Responders

(N=40)

Headache 14 (33.3) 10 (25.0)

Nausea 8 (19.0) 0

Dry Skin 7 (16.7) 0

Fatigue 6 (14.3) 0

Pruritus 6 (14.3) 0

Diarrhea 6 (14.3) 0


19

Abstract #76

High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172/MK-8742 +/- RBV for 12 Weeks in HCV Genotype 1

Infected Patients: The C-WORTHY Study Eric Lawitz1, John M. Vierling2, Abel Murillo3, Marcelo Kugelmas4, Jan Gerstoft5, Peter Winkle6, Luis A. Balart7, Peer B. Christensen8, Reem H. Ghalib9, Ronald Nahass10, Melissa Shaughnessy11, Xiao Sun11,

Peggy Hwang11, Janice Wahl11, Michael Robertson11, Barbara Haber11

1. University of Texas Health Science Center, Texas Liver Institute, San Antonio, TX, United States.

2. Baylor College of Medicine, Houston, TX, United States. 3. Advanced Intervention & Pain Management Research Clinic, Miami, FL, United States.

4. South Denver Gastroenterology, PC, Englewood, CO, United States. 5. Epidemiklinikken, Rigshospitalet, Copenhagen, Denmark.

6. Anaheim Clinical Trials, Anaheim, CA, United States. 7. Tulane University Medical Center, New Orleans, LA, United States.

8. Infektionsmed. Afd Q 2 sal, Odense Universitets Hospital, Odense, Denmark.

20

Study Design

D1 TW12 SVR24SVR4 SVR8TW4 SVR12

n=25

n=13

n=27

Follow-up

Follow-up

Follow-up

MK-5172 (100 mg)+ MK-8742 (20 mg)+ RBV; G1a & G1b

MK-5172 (100 mg)+ MK-8742 (50 mg);

G1b

MK-5172 (100 mg)+ MK-8742 (50 mg)+ RBV; G1a & G1b


21

Virologic Responses

TW4 TW12 SVR4 SVR120

102030405060708090

100100 96 96 9693 93 89 89

100 100 100 100MK-5172 (100 mg) + MK-8742 (20 mg) + RBV (n=25)

MK-5172 (100 mg) + MK-8742 (50 mg) + RBV (n=27)

MK-5172 (100 mg) + MK-8742 (50 mg) (n=13)

% H

CV

-RN

A <

25

IU

/mL

2525

2527

1313

2425

2527

1313

2425

2427

1313

2425

2427

1313

Treatment Follow-up


22

Common Adverse Events During Treatment*

Common Adverse Event

Number of patients (%)

MK-5172 100 mg + MK-8742 20 mg

+ RBVn=25

MK-5172 100 mg + MK-8742 50 mg

+ RBVn=28

MK-5172 100 mg + MK-8742 50 mg

n=12

All armsN=65

Fatigue 8 (32) 5 (18) 4 (33) 17 (26)

Headache 4 (16) 5 (18) 5 (42) 14 (22)

Nausea 3 (12) 7 (25) 2 (17) 12 (18)

Diarrhea 3 (12) 4 (14) 1 (8) 8 (12)

Dizziness 4 (16) 2 (7) 1 (8) 7 (11)

Rash 1 (4) 5 (18) 1 (8) 7 (11)

* Incidence ≥10% in all arms


23

Abstract #LB-20

Rapid and Consistent Virologic Responses in a Phase 2 Trial of a New All-Oral Combination of Faldaprevir, Deleobuvir, and

PPI-668, with and without Ribavirin, in Patients with HCV Genotype-1a Infection

Jacob P. Lalezari1, Laura Holland1, Eileen Glutzer1, Pamela Vig2, Mabrouk Elgadi3, Jerry O. Stern3, Richard Colonno2, Sherin Halfon2, Eric Ruby2, Ningwu Huang2, Qi Huang2, Eileen Nash2, Nathaniel A. Brown2

1. Quest Clinical Research, San Francisco, CA, United States. 2. Presidio Pharmaceuticals, San Francisco, CA, United States.

3. Boehringer Ingelheim, Ridgefield, CT, United States.

24

Objectives

Primary

• To assess the efficacy of 12 weeks of treatment with a new three

investigational drug, all-oral antiviral regimen of PPI-668 (NS5A inhibitor)

added to faldaprevir (protease inhibitor, FDV) and deleobuvir (non-

nucleoside NS5B inhibitor, DBV), with and without ribavirin (RBV), in patients

with HCV gt-1a infection

Secondary

• To assess the efficacy of two dose levels of DBV (600 mg BID vs.

400 mg BID), in the context of a three drug investigational regimen

• To assess the safety/tolerance of each of the treatment regimens Lalezari JP, et al. Abstract #LB-20, AASLD 2013

25

Study Design

Treatment Period PostTreatment Period

Cohort 1(n=12)

Cohort 2(n=12)

Cohort 3(n=12)

Day0

Week 12

Week 16SVR4

Week 24SVR12

Week 36SVR24

Study Design and Methods

600 mg BID DBV + 120 mg QDFDV* + 200 mg QD 668 + RBV

400 mg BID DBV + 120 mg QDFDV* + 200 mg QD 668 + RBV

600 mg BID DBV + 120 mg QDFDV* + 200 mg QD 668 (no RBV)

*FDV loading dose (240 mg) on Day 1Lalezari JP, et al. Abstract #LB-20, AASLD 2013

26

HCV RNA Categorical Responses

Time

<LLOQ/<LLOD (%)1

Cohort 1 n Cohort 2 nCohort 3

(RBV-free) nAll

Cohorts n

Week 2 92/42 12 92/67 12 67/17 12 83/42 36

Week 4 92/75 12 100/100 12 100/67 12 97/81 36

Week 6 100/100 112 100/92 12 100/100 10 100/97 33

Week 8 100/100 112 100/100 11 100/100 4 100/100 26

Week 12 100/100 92 100/100 8 N/A3 0 100/100 17

SVR4 100/100 72 100/100 6 N/A3 0 100/100 13

• Overall, 97% of patients across all three cohorts achieved HCV RNA <LLOQ (81% <LLOD) at week 4, regardless of RBV use

1Percentage based on number of patients achieving LLOQ and LLOD at the indicated time point for each cohort2Excludes 1 patient who discontinued at Week 5 due to viral breakthrough3RBV-free Cohort 3 was initiated later, after efficacy and safety criteria were met in Cohorts 1 and 2

Lalezari JP, et al. Abstract #LB-20, AASLD 2013

27

Safety Observations • Clinical adverse events (AEs) have been similar to those previously seen in

studies of FDV and DBV (skin rashes and GI side effects, mild to moderate

in intensity)

• Patients in the RBV-free cohort (Cohort 3) exhibited a clear predominance of

mild AEs (83% indicated as “mild”) compared with mixed mild-moderate

severity for RBV-containing regimens (Cohorts 1 and 2)

• Grade ≥1 bilirubin elevations were common

– 88% of Cohort 1 and 2 patients, less common in RBV-free Cohort 3 (46%)

Lalezari JP, et al. Abstract #LB-20, AASLD 2013

28

Abstract #215

Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients

with Cirrhosis: the LONESTAR trial

Eric Lawitz1, Fred Poordad1, Robert H. Hyland2, Xiao Ding2, Christy Hebner2, Phil S. Pang2, William T. Symonds2, John G. McHutchison2, Fernando E. Membreno1

1. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States.

2. Gilead Science, Inc, Foster City, CA, United States.

29

Study Design

• Single center study of GT 1 patients• Broad inclusion criteria

– No upper limit to age or BMI

– Platelets ≥50,000/mm3

Ra

nd

om

ize

d

1:1

SOF/LDV

SOF/LDV

SOF/LDV + RBV

SOF/LDV

Treatment Naïve

(No

cirrhosis)

PI Failures

(50% cirrhosis) SOF/LDV + RBV

COHORT 1(n=60)

COHORT 2(n=40)

Wk 0 Wk 8 Wk 12

Ra

nd

om

ize

d

1:1

:1

Wk 24Wk 20

SVR12

SVR12

SVR12

SVR12

SVR12


30

Results: Demographics of Patients Who Previously Failed PI Therapy

• All patients were required to have experienced virologic failure– Patients who stopped prior therapy due to an AE were excluded

PI Failuresn=40

Prior treatment with boceprevir 22/40 (55)

Prior treatment with telaprevir 18/40 (45)

Cirrhosis, n (%) 22/40 (55)

Mean platelet count, x 103/µL 107

Mean albumin, g/dL 3.8


31

SVR12 Results

Series10

20

40

60

80

100 95100 95 95

100

Treatment Naïve(No Cirrhosis)

PI Failures(50% Cirrhosis)

─ ─ ─+ +8 12 128 12

Pat

ient

s (%

)

19/20 21/21 18/19 18/19 21/21

RBVDuration (week)


32

Patients Who Previously Failed Protease Inhibitor Therapy: With and Without Cirrhosis

Se-ries1

0

20

40

60

80

100 95 100 100 10091

100

No Cirrhosis Cirrhosis

─ +RBV12Duration (week)

Pat

ient

s (%

)

18/19 21/21

Overall

10/10 11/118/8 10/11

12 12─ + ─ +


33

Results: Safety Summary

Patients, n (%)SOF/LDV

n=58SOF/LDV+RBV

n=42

Overall safety

AEs 24 (41) 24 (57)

Grade 3-4 AEs 0 6 (14)

Serious AEs 2* (3) 2† (5)

Treatment discontinuation due to AEs

0 0

Laboratoryabnormalities

Grade 3-4 laboratory abnormality

4 (7) 6 (14)

Hemoglobin <10 g/dL 0 8 (19)

Hemoglobin <8.5 g/dL 0 2 (5)

*Peptic ulcer, spinal compression fracture; †Delirium, suicidal ideation.


34

GT 2 and GT 3

35

Abstract #1085

Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial

Stefan Zeuzem1, Geoffrey M. Dusheiko2, Riina Salupere3, Alessandra Mangia4, Robert Flisiak5, Robert H. Hyland6, Ari Illeperuma6, Evguenia S. Svarovskaia6, Diana M. Brainard6, William T. Symonds6, John G.

McHutchison6, Ola Weiland7, Hendrik W. Reesink8, Peter Ferenci9, Christophe Hezode10, Rafael Esteban11

1. Johann Wolfgang Goethe University, Frankfurt, Germany.

2. Royal Free and University College School of Medicine, Royal Free Hospital, London, United Kingdom. 3. Tartu University Hospital, Tartu, Estonia. 4. "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy. 5. Medical University of Bialystok, Bialystok, Poland. 6. Gilead Sciences, Inc., Foster City, CA, United States.

7. Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 8. Academic Medical Center, Amsterdam, Netherlands. 9. Medical University of Vienna, Vienna, Austria. 10. Hôpital Henri Mondor, Créteil, France. 11. Hospital Universitario Val d’Hebron, Barcelona, Spain.

36

Wk 0 Wk 24 SVR4, SVR12, SVR24

Placebo*(n = 85)

Sofosbuvir + Ribavirin (n = 250)

Sofosbuvir + Ribavirin(n = 84)*

*Protocol amended to eliminate placebo arm and to extend treatment duration to 24 weeks for patients with genotype 3 HCV irrespective of prior treatment history.

VALENCE: Study Design

Wk 12

Zeuzem S, et al. Abstract #1085, AASLD 2013

37

0

20

40

60

80

100 97 10091 88

SVR12 in GT 2 Patients Treated for 12 Weeks

SV

R1

2 (

%)

*3 of 11 patients (27%) with HCV GT 3 who received 12 weeks of SOF+RBV achieved SVR 12.


0

20

40

60

80

100 9385

SVR12 in GT 2 and 3 Patients*

SV

R1

2 (

%)

GT 2SOF+RBV 12 wk

GT 3SOF+RBV 24 wk

Naïve,Noncirrhotic

Naïve,Cirrhotic

Experienced,Noncirrhotic

Experienced,Cirrhotic

68/73212/250 29/30 2/2 30/33 7/8

38

SVR12 in GT 3 Patients Treated for 24 Weeks

0

20

40

60

80

100 94 92

87

60

SV

R1

2 (

%)

Naïve,Noncirrhotic

Naïve,Cirrhotic

Experienced,Noncirrhotic

Experienced,Cirrhotic

86/92 12/13 27/4587/100


39

Abstract #LB-4

Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment

Experienced Patients with and without Compensated Cirrhosis: Results from the LONESTAR-2 Study

Eric Lawitz1, 2, Fred Poordad1, 2, Diana M. Brainard3, Robert H. Hyland3, Di An3, William T. Symonds3, John G. McHutchison3, Fernando E. Membreno1, 2

1. Texas Liver Institute, San Antonio, TX, United States. 2. University of Texas Health Science Center, San Antonio, TX, United States.

3. Gilead Science, Inc, Foster City, CA, United States.

40

Study Design

SOF + PEG/RBV SVR12GT 2/3(N=47)

• Study population

– HCV GT 2 or 3

– Failed treatment with pegylated interferon and ribavirin

– Approximately 50% with compensated cirrhosis

– HIV and HBV coinfected patients excluded

Wk 0 Wk 12 Wk 24 Wk 36

Lawitz E, et al. Abstract #LB-4, AASLD 2013

41

Series10

20

40

60

80

100 89 9683

Results: SVR12 by HCV Genotype

Overall GT 2 GT 3

42/47 22/23 20/24

SV

R1

2 (%

)


42

Results: SVR12 by Cirrhosis Status

GT 2 GT 30

20

40

60

80

100100 8393 83

No Cirrhosis CirrhosisS

VR

12

(%)

9/9 13/14 10/12 10/12

Error bars represent 95% confidence intervals.


43

Liver Transplant

44

Abstract #216

Sustained Virological Response After Protease Inhibitor-based Therapy For Hepatitis C Recurrence After Liver

Transplantation: A Multicentric European Experience

Audrey Coilly1, 2, Jerome Dumortier4, Danielle Botta-Fridlund5, Marianne Latournerie6, Vincent Leroy7, Georges-Philippe Pageaux8, Emiliano G. Giostra9, Christophe Moreno10, Bruno Roche1, 3, Pascal Lebray11, Sylvie Radenne12, Anne-Catherine Saouli13, Yvon Calmus14, Laurent Alric15, Maryline Debette-Gratien16, Victor de Ledinghen17, Francois Durand18, Christophe

Duvoux19, Didier Samuel1, 2, Jean-Charles Duclos-Vallee1, 3

1. Centre Hepato-Biliaire, AP-HP, Hopital Paul Brousse, Villejuif, France. 2. Unit 785, Inserm, Villejuif, France. 3. UMR-S785, Univ Paris-Sud, Villejuif, France. 4. Dept Hepato-gastro-enterologie, Hopital Edouard Herriot, Lyon, France. 5. Hepato-gastro-enterologie, AP-HM Hopital de la Conception, Marseille, France. 6. Maladies du foie et de l'appareil digestif, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 7. Hepato-gastro-enterologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. 8. Hepato-gastro-enterologie et Transplantation, CHU - Hopital Saint Eloi, Montpellier, France. 9. Gastro-enterologie et Hepatologie, Hopitaux Universitaire de Geneve, Geneve, Switzerland.

10. Hepato-Gastro-Enterologie, Hopital Erasme - Cliniques Universitaires de Bruxelles, Bruxelles, Belgium. 11. Hepato-gastro-enterologie, AP-HP, Hopital Pitié Salpétrière, Paris, France. 12. Hepato-gastro-enterologie, Hopital de la Croix Rousse, Lyon, France. 13. Hepato-gastro-enterologie, CHRU de Strasbourg, Strasbourg, France. 14. Chirurgie Digestive, AP-HP, Hopital Saint Antoine, Paris, France. 15. Médecine Interne, CHU Purpan, Toulouse, France. 16. Hepato-gastro-enterologie, Centre Hospitalier Régional Universitaire Dupuytren, Limoges, France. 17. Hepatogastroenterologie et Oncologie digestive, CHU de Bordeaux - Hopital Haut Leveque, Pessac, France. 18. Hepato-Gastro-Enterologie, AP-HP, Hopital Beaujon, Clichy, France. 19. Hepato-gastro-enterologie, AP-HP, Hopital Henri Mondor, Creteil, France.

45

Patients and Methods

• Study cohort

• N=79 (who would have achieved SVR12)

• Enrolled between March 2011 and July 2012

• In 17 liver transplant centers in France, Belgium and Switzerland

• Inclusion criteria:

– Genotype 1 active and chronic hepatitis C

– Recurrence defined by a fibrosis stage >1 (METAVIR) or FCH

– Stable immunosuppressive regimen

– No HBV or HIV coinfection

Coilly A, et al. Abstract #216, AASLD 2013

46

Study Design

PegIFN/RBV PegIFN/RBV+BOC(800mg tid)

PegIFN/RBV PegIFN/RBV+TVR (750mg tid)

PegIFN/RBV+TVR (750mg tid)

Week -4 Week 0 Week 4 Week 12

Planned therapy duration: 48 weeks

n=35

n=19

n=25


47

Virological Response

EOT RVS 12 RVS 24

43%41%

27%

60%

51%47%

Tela Boce

n=44 n=35 n=44 n=35 n=38 n=32

p=0.176 p=0.132p=0.373

SVR 12 SVR 24


TVR BOC

48

F0 F1 F2 (n=45) F3 F4 (n=34) F4 (n=18) FCH (n=9)

54%

35% 33% 33%



SVR12 according to fibrosis stage

p=ns

49

G1a (n=25) G1b (n=53) Naïve (n=35) Relapse (n=11) Nul NR (n=17)

44% 45% 46%

55%

29%



SVR12 according to genotype

p=ns

SVR12 according to previous response

50

Abstract #LB-2

Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation:

Preliminary Results of a Prospective, Multicenter Study

1. Mayo Clinic, Rochester, MN, United States. 2. Auckland City Hospital, Auckland, New Zealand. 3. Hannover Medical School, Hannover, Germany. 4. Columbia University, New York, NY, United States. 5. Beth Israel Deaconess Medical Center, Boston, MA, United States. 6. Indiana School of Medicine, Indianapolis, IN, United States. 7. University of Michigan, Ann Arbor, MI, United States.

8. Kansas University Medical Center, Lawrence, KS, United States. 9. NYU Medical Center, New York , NY, United States. 10. Duke University Medical Center, Durham, NC, United States. 11. Gilead Sciences, Foster City, CA, United States. 12. University of California, San Francisco, CA, United States. 13. Université Paris-Sud, Villejuif, France. 14. The Liver Unit, Barcelona, Spain.

Michael R. Charlton1, Edward J. Gane2, Michael P. Manns3, Robert S. Brown4, Michael P. Curry5,Paul Y. Kwo6, Robert J. Fontana7, Richard Gilroy8, Lewis W. Teperman9, Andrew J. Muir10,

John G. McHutchison11, William T. Symonds11, Jill M. Denning11, Lindsay McNair11, Sarah Arterburn11,Norah Terrault12, Didier Samuel13, Xavier Forns14

51

Study Design and Objectives

• Patients with recurrent HCV post-liver transplant, all genotypes

• Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels

• Study objectives– Primary: sustained virologic response 12 weeks post treatment with

sofosbuvir + RBV in liver transplant recipients – Secondary: safety, tolerability and viral kinetics

SOF 400 mg + RBV 400‒1200 mg (N=40) SVR12

Week 0 12 24 36

Charlton MR, et al. Abstract #LB-2, AASLD 2013

52

Results: Virologic Response

Week 4 EOT* SVR 40

20

40

60

80

100100 100

77

39/3940/40 27/35†Viro

logi

c R

espo

nse

Rat

e (%

)

*1 patient still on treatment; †4 patients have not reached SVR4 visit.


53

Concomitant Immunosuppression

• No interactions reported between SOF and any immunosuppressive agents during study

• 4 patients increased tacrolimus dosing during SOF therapy

0

20

40

60

80

100

70

3528 25

511/4028/40 14/40 10/40 2/40

Tacrolimus Mycophenolate mofetil

Prednisone Cyclosporin Azathioprine

Pat

ient

s (%

)


54

Abstract #213

Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation

Michael P. Curry1, Xavier Forns2, Raymond T. Chung3, Norah Terrault4, Robert S. Brown5, Jonathan M. Fenkel6, Fredric D. Gordon7, Jacqueline G. O'Leary8, Alexander Kuo9, Thomas D. Schiano10, Gregory T.

Everson11, Eugene R. Schiff12, Alex Befeler13, John G. McHutchison14, William T. Symonds14, Jill M. Denning14, Lindsay McNair14, Sarah Arterburn14, Dilip Moonka15, Edward J. Gane16, Nezam H. Afdhal1

1. Beth Israel Deaconess Medical Center, Boston, MA, United States. 2. The Liver Unit, Barcelona, Spain. 3. Massachusetts General Hospital, Boston, MA, United States. 4. University of California San Francisco, San Francisco, CA, United States. 5. Columbia University, New York, NY, United States. 6. Thomas Jefferson University Hospital, Philadelphia, PA, United States. 7. Lahey Clinic, Burlington, MA, United States. 8. Baylor University Medical Center, Dallas, TX, United States.

9. University of California San Diego, La Jolla, CA, United States. 10. Mount Sinai School of Medicine, New York, NY, United States. 11. University of Colorado, Denver, CO, United States. 12. University of Miami, Miami, FL, United States. 13. St. Louis University, St. Louis, MO, United States. 14. Gilead Sciences, Foster City, CA, United States. 15. Henry Ford Health System, Detroit, MI, United States. 16. Auckland City Hospital, Auckland, New Zealand.

55

Background and Aims:

• Recurrent HCV infection of the allograft is universal

in patients with detectable HCV RNA at the time of

liver transplantation (LT) and may result in

accelerated progression to cirrhosis and graft loss.

• Interferon-based antiviral treatment before LT can

prevent HCV recurrence, but this treatment is poorly

tolerated and effective in only a minority of patients. Curry MP, et al. Abstract #213, AASLD 2013

56

Methods:

• In this phase 2 open-label study, patients with chronic HCV infection of any

genotype (GT) listed for LT for hepatocellular carcinoma (HCC) received up

to 48 weeks of SOF 400 mg/day and RBV 1000-1200 mg/day before LT.

• All patients had HCC within Milan criteria and well compensated cirrhosis

(Child-Pugh-Turcotte score of ≤7).

• The primary endpoint was virologic response (HCV RNA <25 IU/mL)

12 weeks after LT in patients who had HCV RNA <25 IU/mL at their last

measurement prior to LT (SVR12).

• Post-LT immunosuppressive regimen was tacrolimus plus prednisone with

or without mycophenolate mofetil. Curry MP, et al. Abstract #213, AASLD 2013

57

Results: • 36 patients included in efficacy analysis

• Received a mean of 17.1 (range 3.3 to 33.7) weeks of treatment prior

to LT

• At the time of writing, 26 patients have reached at least 12 weeks post-

transplant, of whom 18 (69%, 90% CI 51% to 84%) achieved SVR12.

• The most frequently reported adverse events were fatigue, anemia,

and rash.

• Two patients discontinued treatment due to AEs of acute renal failure and

pneumonitis, neither was attributed to study drug.

• One SAE, anemia, was considered related to study drug. Curry MP, et al. Abstract #213, AASLD 2013

best of hcv from aasld 2013

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