best of hcv from aasld - ic-hep · best of hcv from aasld rosmawati mohamed, md ... 14/ 15 13/ 13...

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Best of HCV from AASLD Rosmawati Mohamed, MD University Malaysia Kuala Lumpur, Malaysia

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TURQUOISE-II: Regimens of ABT-450/r/Ombitasvir and Dasabuvir With Ribavirin

Achieve High SVR12 Rates in HCV Genotype 1-Infected Patients with Cirrhosis, Regardless

of Baseline Characteristics Michael W. Fried1; Xavier Forns2; Nancy Reau3; Heiner Wedemeyer4; Mitchell L. Shiffman5;

Angeles Castro6; David J. Mutimer7; Samuel S. Lee8; Roger Trinh9; Sandra S. Lovell9; Leticia Canizaro9; Marcos Pedrosa9; Thomas Berg10

1.  University of North Carolina at Chapel Hill UNC Liver Center, Chapel Hill, NC

2.  Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Barcelona, Spain

3.  University of Chicago Medical Center, Chicago, IL 4.  Medizinische Hochschule Hannover, Hannover, Germany 5.  Liver Institute of Virginia, Newport News, VA

6.  Complejo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain

7.  Queen Elizabeth Hospital and NIHR Liver Biomedical Research Unit, Birmingham, United Kingdom

8.  University of Calgary, Calgary, AB, Canada 9.  AbbVie Inc., North Chicago, IL 10. Universitätsklinikum Leipzig, Leipzig, Germany

Abstract #81

3

Background

•  The 3D regimen includes: –  ABT-450 - a potent NS3/4A protease inhibitor.

•  Co-dosing of ABT-450 with ritonavir (r; ABT-450/r) increases the peak, trough, and overall drug exposures of ABT-450, to allow once daily dosing

–  Ombitasvir - a potent NS5A inhibitor

–  Dasabuvir - a non-nucleoside NS5B polymerase inhibitor

Fried M, et al. Abstract #81, AASLD 2014

4

Study Objectives

•  To evaluate the impact of baseline demographic, viral, and disease characteristics on treatment outcomes in patients with compensated cirrhosis

•  Data were derived from TURQUOISE-II: A large, international, phase 3 trial in patients with compensated cirrhosis that evaluated the safety and efficacy of 3 DAAs (3D) + ribavirin (RBV) in treatment-naïve and treatment-experienced genotype 1 (GT1)-infected patients


5

TURQUOISE-II: Overall SVR12 Rates 3D + RBV

91.8 96.5

0

20

40

60

80

100

12-Week 24-Week

SVR

12, %

Pat

ient

s

191/ 208

166/ 172


6

Logistic Regression for Predictors of Not Achieving SVR12

•  Three factors were significantly associated (p<0.05) with lower rates of SVR12 in a logistic regression model

•  Importantly, demographics (eg, age, gender, race, BMI, diabetes), viral factors (baseline HCV RNA), disease related factors (albumin, platelets) were not associated with lower SVR rates

Variable P Value

IL28B TT genotype 0.021 Prior null response 0.038 HCV GT1a 0.046


7

Conclusions:

• GT 1a patients without cirrhosis benefit from RBV inclusion in 12 week treatment regimen (SVR12=96%)

• GT 1a patients with cirrhosis achieved SVR12 rates >90% with 3D + RBV regimen

– Difference between 12 and 24 week duration?

Everson G, et al. Abstract #83, AASLD 2014

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Integrated Efficacy Analysis of Four Phase 3 Studies in HCV Genotype 1a-Infected Patients

Treated with ABT- 450/r/Ombitasvir and Dasabuvir With or Without Ribavirin

Gregory T. Everson1, Geoffrey Dusheiko2, Eoin Coakley3, Stephen D. Shafran4, Fabien Zoulim5, Moises Diago6, Bradley Freilich7, Ravi Ravinuthala8, Suzanne Norris9, Junyuan J. Xiong3, Roger Trinh3, Tolga

Baykal3, Yan Luo3, Mark S. Sulkowski10;

1.  University of Colorado Denver, Aurora, CO; 2.  The Royal Free Hospital, London, United Kingdom; 3.  AbbVie Inc., North Chicago, IL; 4.  University of Alberta, Edmonton, AB, Canada; 5.  Hospices Civils de Lyon, Lyon, France; 6.  Hospital Quirón de Valencia, Valenci, Spain;

7.  Kansas City Gastroenterology & Hepatology, Kansas City, MO; 8.  Consultants for Clinical Research, Cincinnati, OH; 9.  St. James’s Hospital, Dublin, Ireland; 10. Johns Hopkins University, Baltimore, MD

Abstract #83

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Methods

•  1058 patients infected with GT 1a in the PEARL-IV, SAPPHIRE-I, SAPPHIRE-II, or TURQUOISE-II trials

•  363/1058 (25%) of GT 1a treated patients had cirrhosis


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90.1 90.1 96.0 96.0

0

20

40

60

80

100

All Patients Treatment Naïve Prop

ortio

n of

pat

ient

s w

ith S

VR12

(%)

3D + PBO

3D + RBV

SVR12 in GT 1a Non-cirrhotic Patients: 3D Regimen +/- RBV for 12 Weeks

Logistic regression: baseline BMI and treatment regimen (+/- RBV) were significant variables for not achieving SVR

94.0 100

95.4

Relapse PR NR

12 Weeks

Prior PegIFN/RBV Response

p=0.004 p=0.006

182/202

569/593

182/202

403/420

47/ 50

36/ 36

83/ 87


11

SVR12 in GT 1a Cirrhotic Patients: 3D Regimen + RBV for 12 vs 24 Weeks

88.7 92.4 93.3

100

80

95.0 94.6 100 100

92.9

0

20

40

60

80

100

All Patients Treatment Naïve

Relapse Partial Responder

Null Responder

Prop

ortio

n of

pat

ient

s w

ith S

VR12

(%)

12 weeks

24 weeks

3D + RBV

Logistic regression: IL28B TT, prior null, North American region and history of IDU were significant variables for not achieving SVR

p=0.08 p=0.73 p=0.13

126/142

115/121

61/66

53/56

14/15

13/13

11/11

10/10

40/50

39/42

12

Conclusions

• GT 1a patients without cirrhosis benefit from RBV inclusion in 12 week treatment regimen (SVR12=96%)

• GT 1a patients with cirrhosis achieved SVR12 rates >90% with 3D + RBV regimen

– Prior PR null responders may benefit from longer treatment duration


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An Integrated Safety and Efficacy Analysis of >500 Patients with Compensated Cirrhosis Treated with

Ledipasvir/ Sofosbuvir with or without Ribavirin Marc Bourlière1, Mark S. Sulkowski2, Masao Omata3, Stefan Zeuzem4, Jordan J. Feld5, Eric Lawitz6, Patrick Marcellin7, Robert H. Hyland8, Xiao Ding8, Jenny C. Yang8, Steven J. Knox8, Phillip S. Pang8,

Mani Subramanian8, William T. Symonds8, John G. McHutchison8, Alessandra Mangia9, Edward J. Gane10, K. Rajender Reddy11, Masashi Mizokami12, Stanislas Pol13, Nezam H. Afdhal14

1.  Hôpital Saint Joseph, Marseilles, France 2.  Johns Hopkins University, Baltimore, MD 3.  Yamanashi Prefectural Hospital Organization, Yamanashi, Japan 4.  Johann Wolfgang Goethe University, Frankfurt am Main, Germany 5.  Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada 6.  Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX 7.  Hôpital Beaujon, University of Paris, Paris, France 8.  Gilead Science, Inc, Foster City, CA 9.  Liver Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy 10. New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand 11. University of Pennsylvania, Philadelphia, PA 12. Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan 13. Department of Hepatology, Université Paris-René Descartes, Paris, France 14. Beth Israel Deaconess Medical Center, Boston, MA

Abstract #82

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Methods

•  Phase 2 and 3 studies of ledipasvir/sofosbuvir (LDV/SOF) + RBV –  LONESTAR, ELECTRON, ELECTRON-2, 337-0113, ION-1,

ION-2, SIRIUS

•  513 treatment naïve and experienced patients with GT 1 with compensated cirrhosis were included in this pooled analysis

•  Ledipasvir: NS5A inhibitor

•  Sofosbuvir: NS5B inhibitor

Bourlière M, et al. Abstract #82, AASLD 2014

15

Baseline Demographics

Patients, % Treatment Naïve

(n=161)

Treatment Experienced

(n=352)

Total (n=513)

Male 63% 68% 67%

Black 8% 4% 5% Asian 17% 15% 15% GT 1a 53% 63% 60% Prior PI Failure NA 68% 47% Region US 50% 31% 37% Ex-US 50% 69% 63%


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SVR12: LDV/SOF for 12 vs 24 Weeks in Compensated Cirrhotics

96 95 98

0

20

40

60

80

100

Overall 12 Weeks 24 Weeks

SVR

12 (%

)

188/191 305/322 493/513


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Total Treatment

Naïve Treatment

Experienced

Overall SVR12

Duration 12 wk

24 wk

Regimen LDV/SOF

LDV/SOF + RBV

Duration/ ± RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

LDV/SOF: SVR12 by Treatment Regimen

SVR12, %

96% 98% 95%

95% 97% 94%

98% 99% 98%

95% 96% 95%

97% 99% 96%

92% 96% 90%

96% 98% 96%

98% 97% 98%

100% 100% 100%

80 90 100 80 90 100 80 90 100


18

Total Treatment

Naïve Treatment

Experienced

Overall SVR12

Albumin (g/dL)

<3.5

≥3.5

Platelets (x 103/µL)

<75

≥75 – <100

≥100 – <125

≥125

FibroScan >12.5 – ≤20

>20

80 90 100

LDV/SOF: SVR12 by Baseline Characteristics

80 90 100

96% 98% 95%

80 90 100

99%

96%

98%

95%

99%

84% 90%

100%

98%

98%

100%

100%

82%

98%

93%

98%

99%

95%

SVR12, %

96%

97% 95%

98%

98%

95%


19

0

100

200

300

400

500

Baseline FU-4 0

1

2

3

4

Baseline FU-4

0

1

2

3

4

Baseline FU-4

0

100

200

300

400

500

600

Baseline FU-4 0

1

2

3

4

5

6

Baseline FU-4

Med

ian,

g/d

L LDV/SOF: Response of Laboratory Parameters

Med

ian,

g/d

L

Med

ian,

U/L

M

edia

n, ×

103 /µ

L

INR Albumin ALT

Bilirubin Platelets

Med

ian

p <0.0001 p <0.0001 p=0.53

p <0.0001 p <0.0001


20

Conclusions

•  96% of this group of 513 patients with compensated cirrhosis achieved an SVR

• Among treatment-experienced patients, 12 weeks of LDV/SOF resulted in a 90% SVR rate

– Adding RBV or extending treatment duration increased this rate to ≥96%


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Ledipasvir/Sofosbuvir with Ribavirin for the Treatment of HCV in Patients with Decompensated

Cirrhosis: Preliminary Results of a Prospective, Multicenter Study

Steven L. Flamm1, Gregory T. Everson2, Michael Charlton3, Jill M. Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4, John G. McHutchison4, K. Rajender Reddy5, Nezam H. Afdhal6

Abstract #239

1.  Northwestern Feinberg School of Medicine, Chicago, IL

2.  University of Colorado Denver, Aurora, CO

3.  Intermountain Medical Center, Murray, UT

4.  Gilead Sciences, Raleigh, NC

5.  University of Pennsylvania School of Medicine, Philadelphia, PA

6.  Beth Israel Deaconess Medical Center, Boston, MA

22

Study Design

•  108 GT 1 or 4 treatment naïve or treatment experienced patients with decompensated cirrhosis (Child-Pugh class B[7-9]) or C[10-12])

•  Inclusion/exclusion –  No history of major organ transplant, including liver –  No HCC –  Total bili <10 mg/dL, hemoglobin >10 g/dL –  CLcr >40 mL/min, platelets >30,000 x 103/uL

•  LDV/SOF (ledipasvir/sofosbuvir)+ RBV for 12 or 24 weeks

Flamm S, et al. Abstract #239, AASLD 2014

23

87 87 86 89 89 90

0

20

40

60

80

100

Overall CPT B CPT C

12 Weeks 24 Weeks

45/52 42/47 26/30 24/27 19/22 18/20

LDV/SOF + RBV in Decompensated Cirrhosis: SVR12


SVR

12 (%

)

24

Overall Safety Summary

Related SAEs: Anemia, hepatic encephalopathy, peritoneal hemorrhage

CPT B CPT C

Patients, % 12 Weeks (n=30)

24 Weeks (n=29)

12 Weeks (n=23)

24 Weeks (n=26)

Adverse Events (AE) 97% 93% 100% 100%

Grade 3-4 AE 7% 28% 26% 42%

Serious AE 10% 34% 26% 42%

Serious and Related AEs 7% 0 0 8%

Treatment discontinuation due to AE 0 3% 0 8%

Death 3% 7% 9% 4%


25

Conclusions

• LDV/SOF + RBV was generally safe and well tolerated in decompensated cirrhotics

– Extending treatment duration to 24 weeks did not increase SVR rate


26

Once Daily Sofosbuvir with GS-5816 for 8 Weeks with or without Ribavirin In Patients with HCV

Genotype 3 without Cirrhosis Result in High Rates of SVR12: The ELECTRON2 Study

Edward J. Gane1, Robert H. Hyland2, Di An2, John McNally2, Diana M. Brainard2, William T. Symonds2, John G. McHutchison2, Catherine A. Stedman3

1.  Auckland Clinical Studies, Auckland, New Zealand 2.  Gilead Science, Inc, Foster City, CA 3.  Christchurch Clinical Studies Trust, Christchurch, New Zealand

Abstract #79

27

Background

• HCV genotype (GT) 3 is common worldwide and remains a significant disease burden

• GT 3 infection is associated with increased risk of fibrosis progression, steatosis, and hepatocellular carcinoma in patients with cirrhosis

28

Background

+

1. Jacobson IM, et al. New Engl J Med 2013;368:1867-77; 2. Lawitz E, et al. New Engl J Med 2013;368:1878-87; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. EASL 2013, poster 1082. 6. Everson G, et al. EASL 2014, oral presentation.

GS-5816 NS5A inhibitor

GS-5816

SOF Nucleotide polymerase inhibitor

OO N

NH

O

O

P

O

HN

O

O

OH3C

H3C

CH3HO F

CH3

SOF

•  Sofosbuvir (SOF)1,2

–  Potent antiviral activity against HCV GT 1‒6

–  Once-daily, oral, 400-mg tablet

•  GS-58163-5

–  Picomolar potency against HCV GT 1‒6 –  Picomolar potency against all common

NS5A RAVs –  PK supports once-daily dosing

•  SOF + GS-58166

–  Treatment for 12 weeks resulted in high SVR in treatment-naïve patients with HCV GT 1‒6 without cirrhosis

29

Aim

• Evaluate safety and efficacy of SOF + GS-5816 for 8 weeks in treatment naïve non-cirrhotic GT 3 patients

• SOF/GS-5816 (25 or 100 mg) + RBV

Gane E, et al. Abstract #79, AASLD 2014

30

SVR

12 (%

)

100 88 96 100

0

20

40

60

80

100

27/27

SVR12: SOF/GS-5816 (25 or 100 mg) + RBV for 8 Weeks in GT 3 Treatment-naïve Non-cirrhotics

GS-5816, mg RBV

21/24 26/27 26/26

25 ‒

25 +

100 ‒

100 +


31

Conclusions

•  SOF + GS-5816 + RBV for 8 weeks resulted in high SVR12 rates in treatment naïve non-cirrhotic GT3 patients

•  Regimen was well tolerated with no identified safety signal

due to SOF or GS-5816 •  SOF 400 mg + GS-5816 100 mg have been co-formulated

in a fixed-dose combo for Phase 3


32

All-oral 12-week Combination Treatment With Daclatasvir (DCV) and Sofosbuvir (SOF) in Patients Infected with

HCV Genotype (GT) 3: ALLY-3 Phase 3 Study D. R. Nelson; 1; J. N. Cooper; 2; J. P. Lalezari; 3; E. Lawitz; 4; P. J. Pockros; 5; N. Gitlin; 6; B. Freilich;7; Z.

Younes; 8; W. Harlan; 9; R. H. Ghall 10; 0; G. I. Oguchi; 11; P. J. Thuluvath; 12; G. Ortiz-Lasanta; 13; M. Rabinovitz; 14; D. Bernstein; 15; M. Bennett; 16; T. Hawkins; 17; N. Ravendhran ; 18; A. M. Sheikh; 19; P.

Varunok; ; K. V. Kowdley; ; D. Hennicken; ; F. McPhee; ; K. Rana; ; E. A. Hughes; 22;

1.  University of Florida, Gainesville, FL, United States. 2.  !nova Fairfax Hospital, Falls Church, VA, United States. 3.  Quest Clinical Research, San Francisco, CA, United States. 4.  Texas Liver Institute, University of Texas Health Science Center,

San Antonio, TX, United States. 5.  Scripps Clinic, La Jolla, CA, United States. 6.  Atlanta Gastroenterology Associates, Atlanta, GA, United States. 7.  Kansas City Research Institute, Kansas City, MO, United States. 8.  Gastro One, Germantown, TN, United States. 9.  Asheville Gastroenterology Associates, Asheville, NC, United

States. 10. Texas Clinical Research Institute, Arlington, TX, United States. 11. Midland Florida Clinical Research Center, DeLand, FL, United

States. 12. Mercy Medical Center, Baltimore, MD, United States.

13. Fundacion de Investigacion de Diego, Santurce, Puerto Rico, United States.

14. University of Pittsburgh, Pittsburgh, PA, United States. 15. Hofstra North Shore-Long Island Jewish School of Medicine,

Manhasset, NY, United States. 16. Medical Associates Research Group, San Diego, CA, United

States. 17. Southwest CARE Center, Santa Fe, NM, United States. 18. Digestive Disease Associates, Baltimore, MD, United States. 19. Gastrointestinal Specialists of Georgia, Marietta, GA,

United States. 20. Premier Medical Group of Hudson Valley, Poughkeepsie, NY,

United States. 21. Swedish Medical Center, Seattle, WA, United States. 22. Bristol-Myers Squibb Research and Development, Princeton,

NJ, United States.

Abstract #LB-3

33

Methods

•  Treatment naive or experienced GT 3 patients received open-label daclatasvir (pangenotypica NS5A inhibitor) + SOF (pangenotypic nucleotide NS5B inhibitor) once daily for 12 weeks

•  21% of patients were cirrhotic

Nelson D, et al. Abstract #LB-3, AASLD 2014

aPangenotypic: GT 1–6 in vitro and GT 1–4 in clinical trials

34

SVR12: DCV + SOF for 12 Weeks in GT 3 Patients

90 86

0

20

40

60

80

100

SVR

12, %

Treatment Naive Treatment Experienced

91/101 44/51


35

SVR12: DCV + SOF for 12 Weeks in GT 3 Patients With Cirrhosis

SVR

12, %

Overall

96 97 94

63 58 69

0

20

40

60

80

100

Present Absent

Treatment- naive

Treatment- experienced

Present Absent Present Absent

105/109 73/75 32/34 20/32 11/19 9/13


36

Conclusion

• DCV + SOF for 12 weeks achieved high SVR rates in treatment naïve (90%), treatment experienced (86%), and non-cirrhotics (96%) – Lower SVR12(63%) in cirrhotics (further strategies to

optimize response are being evaluated)

• DCV + SOF was safe and well tolerated


37

All-Oral, Fixed-Dose Combination Therapy With Daclatasvir/Asunaprevir/Beclabuvir for Non-Cirrhotic Patients With Chronic HCV Genotype 1 Infection:

UNITY-1 Phase 3 SVR12 Results Poordad F,1 Sievert W,2 Mollison L,3 Bräu N,4 Levin J,5 Sepe T,6 Lee SS,7 Boyer N,8 Bronowicki J-P,9Jacobson IM,10 Boparai N,11 Hughes E,11 Swenson ES,12 Yin PD,12 on behalf of the UNITY-1 Study

Team

Abstract #LB-7

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

2.  Monash Health and Monash University, Melbourne, VIC, Australia.

3.  Fremantle Hospital, Fremantle Hepatitis Services, Fremantle, WA, Australia.

4.  Bronx Veterans Affairs Medical Center, New York, NY, United States.

5.  Dean Foundation, Madison, WI, United States. 6.  University Gastroenterology, Providence, RI, United States. 7.  University of Calgary, Calgary, AB, Canada. 8.  Service d'Hepatologie, Hopital Beaujon, Clichy, France. 9.  Centre Hospitalier Universitaire de Nancy, University de

Lorraine, Vandoeuvre les Nancy, France. 10. Weill Cornell Medical College, New York, NY, United States.

11. Bristol-Myers Squibb, Princeton, NJ, United States. 12. Bristol-Myers Squibb, Wallingford, CT, United States.

38

All-Oral DCV-TRIO Regimen

•  Daclatasvir (DCV) –  Pangenotypic NS5A inhibitor with low potential for drug–drug

interactions –  Safe and well tolerated in > 6000 subjects –  Approved in Europe and Japan; under regulatory review in the US

•  Asunaprevir (ASV) –  NS3 protease inhibitor –  Clinical data in GT 1 and 4

•  Beclabuvir (BCV; BMS-791325) –  Non-nucleoside NS5B polymerase inhibitor –  Clinical data in GT 1 and 4

•  DCV/ASV/BCV co-formulated as fixed-dose combination

NS2

NS4B

NS3 NS5B

Viral RNA

NS5A

NS4A

Poordad F et al. AASLD 2014. Poster LB-7

39

Background

• UNITY-1 Study

– Daclatasvir/Asunaprevir/Declabuvir twice daily in GT 1 treatment naïve and treatment experienced noncirrhotics

Poordad F et al. AASLD 2014. Poster LB-7

40

DCV-TRIO for 12 Weeks: SVR12 in GT 1 Treatment Naïve Noncirrhotic Patients

92 90 98

89 85

100

0

20

40

60

80

100

All GT 1a GT 1b All GT 1a GT 1b

SVR

12 (%

)

287/ 312

________________________________

Treatment Naive ________________________________


206/ 229

81/ 83

92/ 103

64/ 75

28/ 28

Overall SVR12: 91% (379/415) Poordad F, et al. Abstract #LB-7, AASLD 2014

41

Safety Summary

• DCV-TRIO was safe and well tolerated with low rates of SAEs (2%) and AE discontinuations (0.7%)

• Most commonly observed AEs were headache, fatigue, diarrhea and nausea

Poordad F, et al. Abstract #LB-7, AASLD 2014

42

All-oral fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325, ± ribavirin, for patients with chronic HCV genotype 1 infection and compensated

cirrhosis: UNITY-2 Phase 3 SVR12 results A. Muir; 1; F. Poordad; 2; J. P. Lalezari; 3; G. T. Everson; 4; G. J. Dore; 5; P. Kwo; 6; C. Hezode; 7;

P. J. Pockros; 8; A. Tran; 9; A. Ramp; 10; R. Yang; 11; E. A. Hughes; 11; E. S. Swenson; 12; P. D. Yin; 12

1.  Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, United States. 2.  Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 3. Quest Clinical Research, San Francisco, CA, United States. 4.  University of Colorado School of Medicine, Denver, CO, United States. 5.  Kirby Institute , UNSW Australia, Sydney, NSW, Australia. 6.  Indiana University School of Medicine, Indianapolis, IN, United States. 7.  Hopital Henri Mondor , University Paris-Est, Creteil, Creteil, France. 8.  Scripps Clinic, La Jolla, CA, United States. 9.  Centre Hospitalier Universitaire de Nice, Nice, France. 10. University of British Columbia, Vancouver, BC, Canada. 11. Bristol-Myers Squibb, Princeton, NJ, United States. 12. Bristol-Myers Squibb, Wallingford, CT, United States.

Abstract #LB-2

43

Background

• UNITY-2 Study

– Daclatasvir/asunaprevir/declabuvir twice daily, fixed dose combo + RBV in GT 1 treatment naïve and treatment experienced compensated cirrhotics

Muir A, et al. Abstract #LB-2 , AASLD 2014

44

DCV-TRIO +/- RBV for 12 Weeks: SVR12 in GT 1 Treatment Naïve and Treatment Experienced Cirrhotic Patients

93 98

87 93

0

20

40

60

80

100

DCV TRIO DCV TRIO + RBV DCV TRIO DCV TRIO + RBV

SVR

12 (%

)

53/57

________________________________

Treatment Naive ________________________________


54/55 39/45 42/45


45

DCV-TRIO +/- RBV for 12 Weeks: SVR12 in GT 1a vs GT 1b

90 97

86 91 100 100

90 100

0

20

40

60

80

100

DCV TRIO DCV TRIO + RBV DCV TRIO DCV TRIO + RBV

SVR

12 (%

)

36/ 40

17/ 17

________________________________

Treatment Naive ________________________________


38/ 39

30/ 35

32/ 35

15/ 15

9/ 10

10/ 10

GT 1a GT 1b


46

Conclusion

• DCV-TRIO + RBV was safe and well tolerated with low rates of SAEs and AE discontinuations

• Most commonly observed AEs with DCV-TRIO were headache, nausea, diarrhea, and fatigue


47

Efficacy and safety of MK-5172 + MK-8742 ± ribavirin in HCV mono-infected and HIV/HCV co-infected

treatment-naïve, non-cirrhotic patients with hepatitis C virus genotype 1 infection: The C-WORTHY study

(Final results, Parts A and B) Mark S. Sulkowski1, Christophe Hezode2, Jan Gerstoft3, John M. Vierling4, Josep Mallolas5, Stanislas Pol6, Marcelo

Kugelmas7, Abel Murillo8, Nina Weis9, Ronald Nahass10, Oren Shibolet11, Lawrence Serfaty12, Marc Bourlière13, Edwin DeJesus14, Eli. Zuckerman15, Frank Dutko16, Anita Y. Howe16, Melissa

Shaughnessy16, Peggy Hwang16, Janice Wahl16, Michael Robertson16, Barbara A. Haber16;

1.  John Hopkins University School of Medicine, Baltimore, MD; 2.  Henri Mondor Hospital, University of Paris-Est, Creteil, France; 3.  Department of Infectious Diseases, Rigshospitalet, Copenhagen,

Denmark; 4.  Baylor College of Medicine, Houston, TX; 5.  Infectious Diseases Service, Hospital Clinic, Barcelona, Spain; 6.  University of Paris, Hospital Cochin, APHP and INSERM, Unite Hepatol,

Paris, France; 7.  South Denver Gastroenterology, Englewood, CO; 8.  Advanced Medical & Pain Management Research Clinic, Miami, FL;

9.  Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark;

10.  ID Care, Hilllsborough, NJ; 11.  Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center,

Tel-Aviv, Israel; 12.  Hôpital Saint Antoine, APHP and INSERM UMR_938, Université Pierre &

Marie Curie, Paris, France; 13.  Service d’hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille,

France; 14.  Orlando Immunology Center, Orlando, FL; 15.  Liver Unit, Carmel Medical Center, Technion Faculty of Medicine, Haifa,

Israel; 16.  Merck & Co. Inc., Whitehouse Station, NJ

Abstract #236

48

Background

•  Grazoprevir (MK-5172) is a highly potent HCV-specific NS3/4A protease inhibitor

•  Elbasvir (MK-8742) is a highly potent HCV-specific NS5A inhibitor

Treatment-naive, non-cirrhotic 12 weeks ± RBV

(n = 65) Pt. A

Treatment-naive Non-cirrhotic

8-12 weeks ± RBV (n = 94) Pt.B

Treatment-naive Cirrhotic

12-18 weeks ± RBV (n = 123) Pt.B

HIV/HCV Co-infected Non-cirrhotic

12 weeks ± RBV (n = 59) Pt.B

Null Responders Cirrhotic / Non-cirrhotic

12-18 weeks ± RBV (n = 130) Pt.B

Sulkowski M, et al. Abstract #236, AASLD 2014

49

SVR12 Rates in Treatment-naïve, Non-cirrhotic GT 1 Patients

80 93 98 97 87

0 10 20 30 40 50 60 70 80 90

100

SVR

12 (%

)

24 30

43 44

79 85

26 30

28 29

_____________________________________

+RBV +RBV -RBV +RBV -RBV

____________________ HCV Mono-infected HCV/HIV Co-infected

8 Weeks GT 1a

____________________________________________________ ________

12 Weeks GT 1a and 1b


50

Overall Summary

• Once daily grazoprevir + elbasvir +/- RBV for 12 weeks led to SVR12 of 87-98% in treatment-naïve, non-cirrhotic mono- and co-infected patients

• Most common AEs were fatigue, headache, nausea and diarrhea


51

Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients

with cirrhosis or previous null response: Final results of the C-WORTHY Study (Parts A and B)

Eric Lawitz1, Edward J. Gane2, Brian Pearlman3, Edward Tam4, Wayne Ghesquiere5, Dominique Guyader6, Laurent Alric7, Jean-Pierre Bronowicki8, Lorenzo Rossaro9, William Sievert10, Reem H. Ghalib11, Luis A.

Balart12, Fredrik Sund13, Martin Lagging14, Frank Dutko15, Anita Y. Howe15, Melissa Shaughnessy15, Peggy Hwang15, Janice Wahl15, Michael Robertson15, Barbara A. Haber15;

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

2.  Auckland Clinical Studies, Grafton, Auckland, New Zealand; 3.  Atlanta Medical Center, Atlanta, GA; 4.  LAIR Centre, Vancouver, BC, Canada; 5.  Vancouver Island Health Authority, Victoria, BC, Canada; 6.  Department of Hepatology, Rennes University Hospital, Rennes

1 University, Rennes, France; 7.  CHU Purpan, Digest Dept., UMR 152, Toulouse 3 University,

Toulouse, France; 8.  INSERM U954, Centre Hospitalier Universitaire de Nancy,

Université de Lorraine, Vandoeuvre-les-Nancy, France;

9.  University of California, Davis Medical Center, Sacramento, CA; 10. Monash University and Monash Health, Melbourne, VIC,

Australia; 11. Texas Clinical Research Institute, Arlington, TX; 12. Tulane University School of Medicine, New Orleans, LA; 13. Infectious Diseases, Uppsala University, Uppsala, Sweden; 14. Institute of Biomedicine, University of Gothenburg, Gothenburg,

Sweden; 15. Merck & Co., Inc., Whitehouse Station, NJ

Abstract #196

52

Background

•  Grazoprevir (MK-5172) is a highly potent HCV-specific NS3/4A protease inhibitor

•  Elbasvir (MK-8742) is a highly potent HCV-specific NS5A inhibitor

Treatment-naive, non-cirrhotic 12 weeks ± RBV

(n = 65) Pt. A

Treatment-naive Non-cirrhotic

8-12 weeks ± RBV (n = 94) Pt.B

Treatment-naive Cirrhotic

12-18 weeks ± RBV (n = 123) Pt.B

HIV/HCV Co-infected Non-cirrhotic

12 weeks ± RBV (n = 59) Pt.B

Null Responders Cirrhotic / Non-cirrhotic

12-18 weeks ± RBV (n = 130) Pt.B

Lawitz E, et al. Abstract #196, AASLD 2014

53

90 97 97 94 94 91 100 97

0

10

20

30

40

50

60

70

80

90

100

SVR

12 (%

, 95%

CI)

Treatment-naïve patients with cirrhosis

PR-Nulls with or without cirrhosis

12 Weeks 18 Weeks 12 Weeks 18 Weeks

+ RBV No RBV + RBV No

RBV + RBV No RBV + RBV No

RBV

SVR12 Rates in Cirrhotic Treatment-naïve and Null Responder GT 1 Patients


54

Summary

•  SVR12 was 92% (23/25) in null responders with cirrhosis treated for 12 weeks with grazoprevir + elbasvir + RBV

•  High efficacy was achieved regardless of the presence or absence of RBV or extended treatment duration from 12 to 18 weeks

•  Grazoprevir + elbasvir were generally safe and well tolerated


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