2
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
Fried M, et al. Abstract #81, AASLD 2014
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
Fried M, et al. Abstract #81, AASLD 2014
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
Fried M, et al. Abstract #81, AASLD 2014
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
8
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
9
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
Everson G, et al. Abstract #83, AASLD 2014
10
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
Everson G, et al. Abstract #83, AASLD 2014
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
Everson G, et al. Abstract #83, AASLD 2014
13
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
14
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%
Bourlière M, et al. Abstract #82, AASLD 2014
16
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
Bourlière M, et al. Abstract #82, AASLD 2014
17
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
Bourlière M, et al. Abstract #82, AASLD 2014
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%
Bourlière M, et al. Abstract #82, AASLD 2014
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
Bourlière M, et al. Abstract #82, AASLD 2014
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%
Bourlière M, et al. Abstract #82, AASLD 2014
21
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
Flamm S, et al. Abstract #239, AASLD 2014
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%
Flamm S, et al. Abstract #239, AASLD 2014
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
Flamm S, et al. Abstract #239, AASLD 2014
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 +
Gane E, et al. Abstract #79, AASLD 2014
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
Gane E, et al. Abstract #79, AASLD 2014
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
Nelson D, et al. Abstract #LB-3, AASLD 2014
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
Nelson D, et al. Abstract #LB-3, AASLD 2014
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
Nelson D, et al. Abstract #LB-3, AASLD 2014
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 ________________________________
Treatment Experienced
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 ________________________________
Treatment Experienced
54/55 39/45 42/45
Muir A, et al. Abstract #LB-2 , AASLD 2014
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 ________________________________
Treatment Experienced
38/ 39
30/ 35
32/ 35
15/ 15
9/ 10
10/ 10
GT 1a GT 1b
Muir A, et al. Abstract #LB-2 , AASLD 2014
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
Muir A, et al. Abstract #LB-2 , AASLD 2014
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
Sulkowski M, et al. Abstract #236, AASLD 2014
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
Sulkowski M, et al. Abstract #236, AASLD 2014
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
Lawitz E, et al. Abstract #196, AASLD 2014
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
Lawitz E, et al. Abstract #196, AASLD 2014