best of hcv from easl 2014

1

Geoffrey Dusheiko, MDLondon, UK

Best of HCV from EASL 2014

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

2

Abstract #O109

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

The Phase 3 ION-2 Study

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

John G. McHutchison6, Mark Sukowski7, Paul Kwo8

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

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

3

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

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

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

Wk 0 Wk 12 Wk 36Wk 24

LDV/SOF SVR12

LDV/SOF + RBV

LDV/SOF

LDV/SOF + RBV

SVR12

SVR12

SVR12

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

Study DesignGT 1 Treatment-Experienced (ION-2)

4

• Arms were balanced with respect to demographics and baseline characteristics

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


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)

5

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

Error bars represent 95% confidence intervals.


0

20

40

60

80

10094 96 99 99

107/111

12 Weeks 24 Weeks

LDV/SOF + RBV

102/109 108/109

SV

R12

(%

)

110/111

LDV/SOF + RBVLDV/SOF LDV/SOF

6

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

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

0

20

40

60

80

100 93 96 100 9894 97 98 100

Failed PEG/RBV Failed Protease Inhibitor

SV

R12

(%

)

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

12 Weeks 24 Weeks

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

7

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

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

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

8

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

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1. Lawitz E, et al. Lancet. 2014;383:515-23.Kowdley, K. et al. EASL 2014, Abstract #O56

Background and AimsGT 1 Treatment-Naïve (ION-3)

• Short, safe, and effective interferon- and ribavirin-free treatment options for patients with chronic HCV GT 1 infection are currently lacking

• LDV/SOF ± RBV for 8 weeks and LDV/SOF for 12 weeks demonstrated high SVR rates in the Phase 2 LONESTAR study in treatment-naïve HCV patients without cirrhosis1

• To evaluate whether LDV/SOF for 8 weeks is effective for HCV treatment-naïve, non-cirrhotic, GT 1 patients or if RBV or a longer treatment duration of 12 weeks is required to achieve high SVR rate

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• 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)

11

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)

Error bars represent 95% confidence intervals.

12

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

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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

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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

15

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


16

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

17

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

18Gane, 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

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Abstract #O111

Safety and Efficacy of Treatment With the Interferon-free, Ribavirin-free Combination of Sofosbuvir+GS-5816 For 12

Weeks in Treatment Naïve Patients With Genotype 1-6 HCV Infection

G.T. Everson1, T.T. Tran2, W.J. Towner3, M.N. Davis4, D. Wyles5, R. Nahass6, J. McNally7,D.M. Brainard7, L. Han7, B. Doehle7, E. Mogalian7, W.T. Symonds7, J.G. McHutchison7, T. Morgan8,

R.T. Chung9

1University of Colorado Denver, Aurora, CO, 2Cedars-Sinai Medical Center, 3Kaiser Permanente, Los Angeles, CA, 4Digestive CARE, South Florida Center of Gastroenterology, LLC, Wellington, FL, 5University

of California, San Diego, CA, 6ID CARE, Hillsborough, NJ, 7Gilead Sciences, Inc., Foster City, 8VA Long Beach, Long Beach, CA, 9Massachusetts General Hospital, Boston, MA, United States

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Study Design

Everson, G. et al. EASL 2014, Abstract #O111

GT 1(N=55)

GT 3(N=54)

GT 2-6(N=45)

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

Wk 0 Wk 12 Wk 24

SVR12

• Open label– SOF 400 mg + GS-5816 25 mg for 12 weeks

or– SOF 400 mg + GS-5816 100 mg for 12 weeks

• Treatment-naïve patients with HCV GT 1-6 without cirrhosis• No ribavirin administered

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Results: SVR12

Series10

20

40

60

80

100 96 91 93100 100 93

SOF + GS-5816 25 mg SOF + GS-5816 100 mg

SV

R12

(%

)


GT 1 GT 2 GT 3

26/27 28/28 10/11 10/10 25/27 25/27

22

Results: SVR12

Series10

20

40

60

80

100100 100 100

86

100

SOF + GS-5816 25 mg SOF + GS-5816 100 mg

SV

R12

(%

)


GT 4 GT 5 GT 6

7/7 6/7 10/10 4/4 5/51/1

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Conclusions

• SOF + GS-5816 for 12 weeks resulted in SVR12 rates >90% in all HCV genotypes (1-6)– Relapse was observed more often in patients treated with

GS-5816 25 mg (N=3) compared to GS-5816 100 mg (N=1)

• The presence of pre-treatment NS5A variants was not predictive of failure to achieve SVR 12

• SOF + GS-5816 was well tolerated with no discontinuations due to AEs

• The combination of SOF 400 mg and GS-5816 100 mg is being evaluated in treatment-experienced patients and patients with cirrhosis


24

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

25

• 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)

26

SV

R12

, %

Pat

ien

ts

All Patients

96.2% 95.3% 98.0%

455/473 307/322 148/151

GT1a GT1b

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

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

27

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

SVR12 455/473 (96.2)

Non-SVR12 18/473 (3.8)

Virologic failure

Breakthrough 1/473 (0.2)

Relapse 7/463 (1.5)

Prematurely discontinued study drug* 7/473 (1.5)

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

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

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

SAPPHIRE-I: Reasons for Non-SVR12

28

Abstract #O163

TURQUOISE-II: SVR12 Rates of 92%-96% in 380 Hepatitis C Virus Genotype 1-Infected Adults With Compensated Cirrhosis Treated With ABT-450/r/ABT-267 and ABT-333 Plus Ribavirin

(3D+RBV)

F. Poordad1, C. Hezode2, R. Trinh3, K.V. Kowdley4, S. Zeuzem5, K. Agarwal6, M.L. Shiffman7,H. Wedemeyer8, T. Berg9, E.M. Yoshida10, X. Forns11, S.S. Lovell3, B. Da Silva-Tillmann3,

A.L. Campbell3, T. Podsadecki3

1The Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2Henri Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3AbbVie Inc., North Chicago, IL,

4Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5J.W. Goethe University, Frankfurt, Germany, 6Institute of Liver Studies, Kings College Hospital, London, United Kingdom,

7Liver Institute of Virginia, Newport News, VA, United States, 8Medizinische Hochschule Hannover, Hannover, 9Universit_tsklinikum Leipzig, Leipzig, Germany, 10University of British Columbia, Vancouver, BC,

Canada, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

29


• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively)

Day 0 Week 24Week 12

SVR12

SVR12

3D + RBV(N=208)

3D + RBV(N=172)

All patients to be followed through 48 weeks post-treatment

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

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

30

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

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

0

20

40

60

80

100S

VR

12,

% P

atie

nts

12 Weeks3D + RBV

91.8

191/208

95.9

165/172

24 Weeks3D + RBV

P=0.089

31

0

20

40

60

80

10092.2

12-week arm

24-week arm

92.9

Naïve Prior RelapseResponse

3D + RBV

SV

R12

, %

Pat

ien

ts

59/64 14/1552/56 13/13

93.3 100 100 100 80.0 92.9

11/11 40/5010/10 39/42

Prior PartialResponse

Prior NullResponse

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

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

32

Abstract #O114

Results Of The Phase 2 Study M12-999:Interferon-Free Regimen Of ABT-450/r/ABT-267+ABT-

333+Ribavirin In Liver Transplant Recipients With Recurrent HCV Genotype 1 Infection

P. Kwo1, P. Mantry2, E. Coakley3, H. Te4, H. Vargas5, R. Brown Jr.6, F. Gordon7, J. Levitsky8, N. Terrault9, J. Burton Jr10, W. Xie3, C. Setze3, P. Badri3, R.A. Vilchez3, X. Forns11

1Indiana University, Indianapolis, IN, 2The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, 3AbbVie Inc., North Chicago, 4University of Chicago Medicine, Chicago, IL, 5Mayo Clinic, Phoenix, AZ,

6Columbia University Medical Center Center for Liver Disease and Transplantation, New York, NY, 7Lahey Hospital & Medical Center, Burlington, MA, 8Northwestern University Comprehensive Transplant Center,

Chicago, IL, 9University of California, San Francisco, San Francisco, CA, 10University of Colorado, Denver, Aurora, CO, United States, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

33


• RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol

Day 0 Week 24

SVR12

To Week 72

3D + RBV(N=34)

Kwo, P. et al. EASL 2014, Abstract #O114

Study M12-999: Design

34Kwo, P. et al. EASL 2014, Abstract #O114

Calcineurin Inhibitor (CNI) Dosing With 3D Regimen • Based on previous drug-drug interaction findings,

recommended dosing during 3D treatment was:

– TAC

• 0.5 mg once weekly or

• 0.2 mg every 3 days

– CYA

• 1/5 of the daily pre-3D treatment dose given once daily

35

Study M12-999: Preliminary Efficacy Results

• No patient had breakthrough• One patient had a relapse (post-treatment day 3)

– At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline


0

20

40

60

80

100

% P

atie

nts

100%

34/34

97.0%

34/34

100% 96.2%

32/33 25/26

SVR4 SVR12RVR(Week 4)

EOTR(Week 24)

36

• An IFN-free, 24-week regimen of ABT-450/r/ombitasvir + dasabuvir + RBV achieved high response rates in immunosuppressed liver transplant recipients with recurrent HCV GT1 infection

• In this on-going study:

– 100% achieved RVR (34/34) and EOTR (34/34)

– 97.0% (32/33) achieved SVR4 and 96.2% (25/26) achieved SVR12

• The regimen was generally well tolerated with 1 patient discontinuing study drug due to AEs

– No deaths, graft losses, or episodes of rejection

• CNI dosing was manageable over the period of the study

Study M12-999: Conclusions


37

Abstract #O58

Results From the Phase 2 PEARL-I Study: Interferon-Free Regimens of ABT-450/R + ABT-267 With or

Without Ribavirin in Patients With HCV Genotype 4 Infection

C. Hezode1, P. Marcellin2, S. Pol3, T. Hassanein4, K. Fleischer-Stepniewska5, T. Baykal6, T. Wang6,S.S. Lovell6, T. Pilot-Matias6, R.A. Vilchez6

1Assistance Publique Hopitaux de Paris, Paris, 2Hopital Beaujon Inserm Crb3 - U 773 - Service Hepatologie, Clichy, 3Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France, 4Southern California

Liver Centers and Southern California Research Center, Coronado, CA, United States, 5EMC Instytut Medyczny Spolka Akcyjna, Wroclaw, Poland, 6AbbVie Inc., North Chicago, IL, United States

38

PEARL-I: Study DesignSubstudy 1*No Cirrhosis

Substudy 2*CompensatedCirrhosis

*Planned number of patients: 40 per treatment armABT-450/r (150/100 mg qd); ombitasvir (25 mg QD); RBV (weight-based 1000 or 1200 mg/day divided BID)All patients followed through 48 weeks post-treatment

Group 1 (GT4)(n=44)

Group 2 (GT1b)(n=42)


Group 4 (GT4)(n=42)

Group 5 (GT4)

Group 6 (GT4)(n=49)

Baseline Week 12 Week 24

ABT-450/r + OmbitasvirTreatment-Naïve

ABT-450/r + OmbitasvirNull Responders

ABT-450/r + Ombitasvir + RBVTreatment-Naïve

ABT-450/r + OmbitasvirPartial/Null Responders & Relapsers

ABT-450/r + Ombitasvir + RBVPartial/Null Responders & Relapsers




ABT-450/r + OmbitasvirPartial/Null Responders & Relapsers


Hezode, C. et al. EASL 2014, Abstract #O58

39

0

20

40

60

80

10097.7%

Pat

ien

ts (

%)

ABT-450/r + Ombitasvir(N=44)

ABT-450/r + Ombitasvir+ RBV(N=42)

SVR4

SVR12

RVR (Week 4)

EOTR (Week 12)

95.5%93.2% 90.9%

97.6% 100% 100% 100%

4344

4244

4144

4044

4142

4242

4242

4242

PEARL-I GT4-Infected Treatment-Naïve Patients: ITT Efficacy Analysis


40

0

20

40

60

80

100

Pat

ien

ts (

%)

ABT-450/r + Ombitasvir + RBV(N=49)

100% 100% 100%

49/49 49/49 37/37

SVR4

RVR (Week 4)

EOTR (Week 12)

PEARL-I GT4-Infected Treatment-Experienced Patients: ITT Efficacy Analysis


41

PEARL-I GT4-Infected Patients:Conclusions

• All-oral, IFN-free, 12-week regimens of ABT-450/r + ombitasvir resulted in:– High SVR12 rates in treatment-naïve HCV GT4-

infected patients• 90.9% with ABT-450/r + ombitasvir

• 100% with ABT-450/r + ombitasvir + RBV

– An SVR4 rate of 100% in treatment-experienced patients receiving ABT-450/r + ombitasvir + RBV

• 12-week regimens of ABT-450/r + ombitasvir +/- RBV were generally well-tolerated, with no study drug discontinuations or interruptions due to AEs, and few decreases in hemoglobin <10 g/dL


42

Abstract #O10

Safety and Efficacy of the All-oral Regimen of MK-5172/MK-8742 + Ribavirin in Treatment-naïve, Non-cirrhotic Patients With Hepatitis C Virus Genotype 1

Infection: The C-WORTHy Study

C. Hezode1, L. Serfaty2, J.M. Vierling3, M. Kugelmas4, B. Pearlman5, W. Sievert6, W. Ghesquiere7,E. Zuckerman8, F. Sund9, M. Shaughnessy10, P. Hwang10, J. Wahl10, M.N. Robertson10, B. Haber10

1Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, 2Gastroenterology and Hepatology, H_pital Saint Antoine, APHP and INSERM UMR_938, Universit_ Pierre

& Marie Curie, Paris, France, 3Hepatology, Baylor College of Medicine, Houston, TX, 4South Denver Gastroenterology, PC, Englewood, CO, 5Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, United

States, 6Gastrointestinal and Liver Unit, Monash University, Clayton, VIC, Australia, 7Vancouver Island Health Authority, Victoria, BC, Canada, 8Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel,

9Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden, 10Merck, Whitehouse Station, NJ, United States

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Aim: C-WORTHy TN


• To assess the efficacy/safety of an 8- to 12-week regimen of MK-5172 + MK-8742 ± weight-based ribavirin in treatment-naïve, noncirrhotic patients with HCV G1 infection

• Key inclusion/exclusion criteria:– Treatment-naïve patients ≥ 18 years old with chronic HCV G1a or G1b infection– Liver biopsy or noninvasive test (METAVIR F0-F3)– Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males)– HIV and hepatitis B virus negative– Alanine aminotransferase (ALT) as aspartate aminotransferase (AST) <350 IU/L

Treatment-naïve, noncirrhotic 12 weeks ± RBV

(n=65)

Treatment-naïve Noncirrhotic

8-12 weeks ± RBV(n=94)

Treatment-naïveCirrhotic

12-18 weeks ± RBV(n=123)

Null respondersCirrhotic/noncirrhotic

12-18 weeks ± RBV(n=130)

HIV/HCV coinfected Noncirrhotic

12 weeks ± RBV(n=59)

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Study Design

SVR, sustained virologic response; TW = treatment week.Hezode, C. et al. EASL 2014, Abstract #O110

RBV-Containing Regimen RBV-Free Regimen

MK-5172 (100 mg)MK-8742 (20 mg)+ RBV

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

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

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

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

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

PART ASVR24

(AASLD 2013)

PART BFollow-up ongoing

SVR4/8

at ≥SVR4(28/30 SVR8)

100% at SVR8

Study Week

Pa

rt A

Pa

rt B

G1a/bN=25

G1a/bn=27

G1bn=13

G1an=30

G1a/bn=33

G1an=31

D1 TW4 TW8 TW12 SVR4 SVR8 SVR12 SVR24

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C-WORTHy (A+B) – Overall Efficacy (SVR4-24)*Intention-to-Treat (Nonvirologic Discontinuation = Failure)

Treatment Week 4 End of Treatment SVR0

25

50

75

100100 100

83

95 96 94100 100 98

8 weeks with RBV 12 weeks with RBV 12 weeks (no RBV)

HC

V R

NA

BL

OQ

(<

25

IU

/mL

), %

Pa

tie

nts

*Part A: 100% of patients have completed SVR24; Part B: 8-week arm, 93% of patients have completed SVR8; 12-week arms, 100% of patients have completed SVR8; 2 patients (Part A), 2 patients (Part B) discontinued early (and are counted as failures).Hezode, C. et al. EASL 2014, Abstract #O110

4-24

30/30 81/85 44/44 30/30 82/85 44/44 25/30 80/85 43/44

46

Summary

• Efficacy

– MK-5172/MK8742 once daily with or without RBV for 12 weeks is highly efficacious with a SVR of 94%-98%

– MK-5172/MK-8742 + RBV for 8 weeks in patients with HCV G1a infection had an SVR44/8 of 83%

– Most common type of virologic failure was relapse after a treatment duration of 8 weeks

• Safety

– All treatment regimens were generally safe and well-tolerated

– There were no early discontinuations due to drug-related Aes

– No grade 3 or 4 laboratory abnormalities


47

Abstract #O63

Efficacy and Safety of the All-Oral Regimen, MK-5172/MK-8742 +/- RBV For 12 Weeks in GT1 HCV/HIV Co-Infected

Patients: The C-WORTHY Study

Mark Sulkowski1, Josep Mallolas2, Marc Bourliere3, Jan Gerstoft4, Oren Shibolet5, Ronald Nahass6, Edwin DeJesus7, Melissa Shaughnessy8, Peggy Hwang8, Barbara Haber8

1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Hospital de Dia. Enfermedades Infecciosas, Barcelona, Spain; 3Service d'hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille,

France; 4Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; 5Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; 6ID Care, Hillsborough, NJ, USA;

7Orlando Immunology Center, Orlando, Florida; 8Merck & Co., Inc., Whitehouse Station, NJ, USA.

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• Globally, ~7 million patients are co-infected with HIV and HCV(1)

• HIV/HCV co-infected patients have a higher rate of progression to cirrhosis and hepatic decompensation than HCV mono-infected patients(1-4)

• MK-5172 and MK-8742 can be dosed with raltegravir + dual NRTI (tenofovir or abacavir + emtricitabine or lamivudine) without dosage adjustments

• MK-5172/MK-8742 has the potential to provide an all-oral, highly efficacious, simple, and well-tolerated regimen

C-WORTHy: MK-5172/MK-8742 ± RBV in 471 HCV G1-infected patients

Treatment-naive, non-cirrhotic12 weeks ± RBV

(n = 65)

Treatment-naive Non-cirrhotic

8-12 weeks ± RBV(n = 94)

Treatment-naive Cirrhotic

12-18 weeks ± RBV(n = 123)

HIV/HCV co-infectedNon-cirrhotic

12 weeks ± RBV(n = 59)

Null responders Cirrhotic / Non-cirrhotic

12-18 weeks ± RBV(n = 130)

1. Sulkowski, et al., Clin Infect Dis. 30 (Suppl 1):S77, 2000; 2. Rockstroh JK, et al., Am J Gastroenterol. 91:2563, 1996; 3. DHHS Antiretroviral Guidelines; for Adults and Adolescents. February, 2013; 4. Naggie S, et al. Gastroenterology. 142:1324, 2012Sulkowski, M. et al. EASL 2014, Abstract #O63

Background

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MK-5172 + MK-8742 + RBV

MK-5172 + MK-8742 (No RBV)

N = 29

N = 30

Follow-up

Follow-up

D1 TW12 SVR12TW4TW2 TW8 SVR24SVR4

Primary endpoint

MK-5172 (100 mg QD) + MK-8742 (50 mg QD); 12 weeks

Sulkowski, M. et al. EASL 2014, Abstract #O63

Study DesignHIV/HCV Co-infected Non-cirrhotic Patients

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TW4 TW8 TW12 SVR40

102030405060708090

100100 100 100 97100

90 90 90

MK-5172 + MK-8742 + RBV (n=29)

MK-5172 + MK-8742 (No RBV; n=30)

Week

% H

CV

RN

A <

25 I

U/m

L

2929

28 29

2929

2929

3030

2629*

2730

2730

Virologic Failures: 1 relapse in +RBV arm; 2 breakthrough and 1 lost to follow up in No RBV arm

* One patient has not yet reached FU4


Virologic Responses ITT Population

51

Summary

Efficacy• Treatment with MK-5172 + MK-8742 ± RBV for 12 weeks demonstrated high

efficacy (90-97% 4 weeks after end-of-treatment; SVR4)

• Three of 59 patients experienced virologic failure

– 1 relapse, 2 breakthrough

Safety• MK-5172 + MK-8742 ± RBV was generally safe and well tolerated in co-

infected patients

• The most common AEs in co-infected patients were headache and asthenia

• All co-infected patients had suppressed HIV and stable CD4 counts

• There were no early discontinuations due to drug-related adverse events

Overall• Observed efficacy and safety in patients with HIV/HCV coinfection was similar

to other patient populations in C-WORTHy


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