1 This activity has been supported by an independent medical education grant from Bristol Myers...

1

Best of HCVFrom AASLD 2013

This activity has been supported by an independent medical education grant from Bristol Myers Squibb.

2013 IC-HEP Educational supporters include Bristol Myers Squibb and Janssen Therapeutics EMEA. Supporters do not influence IC-HEP faculty selection or educational content.

Paul Kwo, MDIndianapolis, Indiana, USA

2

Abstract #LB-1

Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve

patients with chronic HCV genotype 1 infection

Gregory T. Everson1, Karen D. Sims2, Paul J. Thuluvath3, Eric Lawitz4, Tarek Hassanein5,Maribel Rodriguez-Torres6, Trevor Hawkins7, Howard Schwartz8, Vinod K. Rustgi9, Federico Hinestrosa10,

James M. Levin11, Zobair M. Younossi12, Lynn R. Webster13, Timothy Eley2, Shu-Pang Huang14,Fiona McPhee15, Dennis M. Grasela2, David F. Gardiner2

1. University of Colorado Denver, Aurora, CO, United States. 2. Bristol-Myers Squibb, Hopewell, NJ, United States. 3. Mercy Medical Center, Baltimore, MD, United States. 4. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 5. Southern California Liver Centers, Coronado, CA, United States. 6. Fundación de Investigación, San Juan, Puerto Rico,United States. 7. Southwest CARE Center, Santa Fe, NM, United States. 8. Miami Research Associates, South Miami, FL, United States.

9. Metropolitan Research, Arlington, VA, United States. 10. Orlando Immunology Center, Orlando, FL, United States. 11. Dean Foundation for Health, Research and Education, Inc, Madison, WI, United States. 12. Inova Fairfax Hospital, Center for Liver Diseases,Falls Church, VA, United States. 13. CRI Lifetree, Salt Lake City, UT, United States. 14. Bristol-Myers Squibb, Princeton, NJ, United States. 15. Bristol-Myers Squibb, Wallingford, CT, United States.

3

• Daclatasvir (DCV)– NS5A replication complex inhibitor with potent, pan-genotypic activity in vitro– Studied in over 5500 patients

• Asunaprevir (ASV)– NS3 protease inhibitor active against genotypes (GT) 1, 4, 5, and 6 in vitro– Studied in over 2000 patients

• BMS-791325– Non-nucleoside, NS5B polymerase inhibitor active against GT 1, 3, 4, 5, and

6 in vitro– Studied in over 500 patients

Direct-Acting Antiviral Agents

Everson GT, et al. Abstract #LB-1, AASLD 2013

4

Randomized, Phase 2b Open-Label Study (AI443-014)

• Patients: treatment-naive, stratified by GT 1a/1b and presence of biopsy-confirmed cirrhosis (82% GT1a and 9% cirrhotics).

• Primary end point: HCV RNA < LLOQ 12 weeks post-treatment (SVR12)

– Observed analysis: breakthrough, relapse, addition of pegIFNα/RBV = failure

– Modified intent-to-treat analysis: missing, breakthrough, relapse or addition of pegIFNα/RBV = failure


DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BID

DCV 30 mg BID + ASV 200 mg BID + BMS-791325 150 mg BID

12-week follow-upAdditional

follow-up to SVR48

0 12 24

N = 80

N = 86

Week

Primary endpoint: SVR12

5

Efficacy Through SVR12 (Observed)

Series10

20

40

60

80

100

End of Treatment SVR4 SVR12

Res

pons

e, %

of p

atie

nts

DCV + ASV + ‘325 75 mg

DCV + ASV + ‘325 150 mg

97.5 94.2 92.4 91.7 92.2 91.7

78/80 81/86 73/79 77/84 71/77 77/84


6

Event, n (%)

DCV + ASV + ‘325 75 mg

N = 80

DCV + ASV + ‘325 150 mg

N = 86Total

N = 166Serious AEs 1 (1.3) 2 (2.3) 3 (1.6)AEs leading to discontinuation 1 (1.3) 1 (1.2) 2 (1.1)Grade 3/4 AEs 0 1 (1.2) 1 (0.5)Most frequent on-treatment AEs (≥ 10%)

Headache 17 (21.3) 24 (27.9) 41 (24.7)Diarrhea 12 (15.0) 13 (15.1) 25 (15.1)Fatigue 12 (15.0) 7 (8.1) 19 (11.4)Nausea 10 (12.5) 7 (8.1) 17 (10.2)

Grade 3/4 lab abnormalitiesAspartate aminotransferase (AST) 1 (1.3) 0 1 (0.5)Glucose, fasting serum (high) 1 (1.3) 1 (1.2) 2 (1.2)Phosphorus, inorganic 0 1 (1.2) 1 (0.5)Bilirubin, total 0 1 (1.2) 1 (0.5)

Safety Outcomes


7

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.

8

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

9

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.

10

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

11

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

12

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

13

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


14

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

15

• 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


16

Abstract #73

Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial

Edward J. Gane1, Catherine A. Stedman2, Robert H. Hyland3, Xiao Ding3, Evguenia S. Svarovskaia3, Phil S. Pang3, William T. Symonds3

1. Auckland Clinical Studies, Auckland, New Zealand. 2. Christchurch Clinical Studies Trust, Christchurch, New Zealand.

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

17

Direct Acting Antiviral Agents

GS-9669• HCV NS5B non-nucleoside inhibitor, binding at thumb site II of the polymerase• Potent antiviral activity with QD dosing • Nanomolar potency against GT 1a and 1b

Sofosbuvir/Ledipasvir FDC• Once daily, oral fixed-dose (400/90 mg)

combination tablet• No food effect• >2000 patients treated

SOFNucleotidePolymeraseinhibitor

LDVNS5Ainhibitor

Gane EJ, et al. Abstract #73, AASLD 2013

18

Study Design

• Primary endpoint: SVR12 (HCV RNA <LLOQ)• Patients enrolled in ELECTRON or ELECTRON 2 (GT1, F3/F4)• All groups were open label

GT 1 Experienced

GT 1 Naïve

Wk 0 Wk 6 Wk 12

F4

F3/F4

F0/F1/F2

SOF/LDV FDC (n=10)

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

SOF/LDV FDC + RBV (n=10)



Ran

dom

ized

Ran

dom

ized SVR12


19

SVR 12 Results: GT 1 Treatment-Experienced Patients with Advanced Fibrosis/Cirrhosis

SOF/LDV SOF/LDV + RBV0

102030405060708090

100

70

100

SV

R 1

2 (

%)

SOF/LDV + RBV SOF/LDV + GS9669

100 100

Duration (wk) 12 12

F4 only F3/F4

12 12

7/10 9/9 25/25* 26/26*

*From ELECTRON 2Gane EJ, et al. Abstract #73, AASLD 2013

20

SVR12 Results: Treatment DurationGenotype 1, Treatment-naïve, No Cirrhosis

SOF + LDV + RBV* SOF/LDV + RBV SOF/LDV + RBV0

102030405060708090

100100 100

68

SV

R 1

2 (

%)

*Gane et al. EASL 2013. †Lawitz et al, Abstract #215, AASLD 2013 (LONESTAR)


Duration (wk) 12 8 6

25/25 21/21 17/25

†

21

Conclusions

• In treatment-experienced patients with advanced fibrosis/cirrhosis, either RBV or GS-9669 may enhance the efficacy of SOF/LDV given for 12 weeks

• The optimal duration of SOF/LDV in treatment-naïve GT 1 patients, even with the addition of RBV, is more than 6 weeks

• Regimens of SOF/LDV alone, or with RBV or GS-9669, were safe and well tolerated


22

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.

23

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

24

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


25

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


26

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 (

%)


27

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


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.


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

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.


35

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

36

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 (%

)


37

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.


38

Patients, n (%)SOF + PEG/RBV

12 weeks(N=47)

Overall safety

AEs 45 (96)

Grade 3-4 AEs 15 (32)

Serious AEs 4 (9)

Treatment discontinuation due to AEs 2 (4)

Hematologic abnormalities

Grade 3-4 laboratory abnormality 28 (60)

Hemoglobin <10 g/dL 13 (28)

Hemoglobin <8.5 g/dL 4 (9)

Absolute neutrophil count <750/mm3 13 (28)

Platelets <50,000/mm3 7 (15)

Results: Adverse Events


39

Conclusions

• SOF + PEG/RBV for 12 weeks demonstrated high efficacy in treatment-experienced GT 2/3 patients who have historically low response rates and limited treatment options

– SVR rates were similar in patients with and without cirrhosis

• SOF + PEG/RBV was generally safe and well tolerated

– Safety profile consistent with PEG/RBV treatment

– Low discontinuation rates

39


40

Abstract #1085

Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patientswith 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.

41

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

42

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

43

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


44

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

45

Background• Reinfection of the transplanted liver is universal in patients who are serum

HCV RNA-positive at the time of transplantation

• Recurrence of HCV is the most common cause of mortality and graft loss following transplantation– 10–50% of patients with recurrent infection progress to cirrhosis within 5

years1

• Once cirrhosis is established, the probability of liver graft failure is 42% within 12 months2

• Current therapies for HCV treatment used after transplantation have poor tolerance, poor efficacy, severe adverse reactions, and significant interactions with immunosuppression medications

1. Berenguer M, et al. Clin Liver Dis 2007;11:355–76; 2. Berenguer M, et al. Hepatology 2002;36:202-10. Charlton MR, et al. Abstract #LB-2, AASLD 2013

46

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

47

Key Inclusion/Exclusion Criteria• Inclusion criteria

– Liver transplant ≥6 and ≤150 months prior to enrollment

– Treatment-naïve or experienced

– CPT ≤7 and MELD ≤17

– Primary or secondary, liver alone or liver-kidney transplant

– Absence of organ rejection

• Exclusion criteria

– Current signs of decompensation

– Use of corticosteriods at any dose >5 mg of prednisone/day


48

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.


49

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 (%

)


50

Grade 3 and 4 Laboratory Abnormalities

n (%)SOF + RBV

N=40

Overall Grade 3 10 (25)

Overall Grade 4 11 (28)

Lymphocytes (4 G3; 9 G4) 13 (33)

Hemoglobin (G3) 8 (20)

Hyperglycemia (3 G3; 1 G4) 4 (10)

White blood count (G3) 3 (8)

Hyperbilirubinemia (G4) 1 (3)

Lipase (G4) 1 (3)

Neutrophil (G3) 1 (3)

AST (G3) 1 (3)


51

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.

52

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

53

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

54

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

1 This activity has been supported by an independent medical education grant from Bristol Myers...

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