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All-Oral Treatment With Daclatasvir Plus Sofosbuvir Plus Ribavirin for 12 or 16 Weeks in
HCV Genotype 3-Infected Patients With Advanced Fibrosis or Cirrhosis: The ALLY-3+ Phase 3 Study
Leroy V,1 Angus P,2 Bronowicki JP,3 Dore G,4 Hézode C,5 Pianko S,6 Pol S,7 Stuart K,8 Tse E,9 McPhee F,10 Bhore R,11 Jimenez-Exposito MJ,11 Thompson A4
1CHU de Grenoble, La Tronche, France; 2Austin Hospital, Heidelberg, Australia; 3CHU Nancy & Lorraine University, Nancy, France; 4St. Vincent’s Hospital and Kirby Institute, Sydney, Australia; 5CHU Henri Mondor, Créteil, France;
6Monash Medical Centre, Clayton, Australia; 7Hôpital Cochin, Paris, France; 8Gallipoli Medical Research Foundation, Greenslopes, Australia; 9Royal Adelaide Hospital, Adelaide, Australia; 10Bristol-Myers Squibb Research
& Development, Wallingford, CT; 11Bristol-Myers Squibb Research & Development, Princeton, NJ.
The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015
Oral LB-3Mercury-Nr: 1392DE15NP07880-04Date of preparation: Nov-2015
■ HCV GT 3 infection is associated with rapid fibrosis progression, a high prevalence of steatosis, and a high risk of hepatocellular carcinoma1
■ HCV GT 3-infected patients with advanced fibrosis, especially those with cirrhosis, remain a population in urgent need of optimally effective therapies
■ In ALLY-3 (AI444218), the pangenotypic, all-oral, RBV-free regimen of DCV + SOF for 12 weeks achieved 96% SVR12 in non-cirrhotic patients; 63% SVR12 was achieved in cirrhotic patients2
■ ALLY-3+ (AI444326) investigated DCV + SOF + RBV for 12 or 16 weeks in GT 3-infected patients with advanced fibrosis (F3) or compensated cirrhosis (F4)
Background
1. Probst A, et al. J Viral Hepat 2011;18:745-759.2. Nelson DR, et al. Hepatology 2015;61:1127–1135.
ALLY-3+
2
ALLY-3+ Study DesignALLY-3+
Phase 3b, open-label, randomized study
Primary efficacy endpoint: SVR12 ■ HCV RNA <LLOQTD/TND (next observation carried backward) by Roche COBAS TaqMan v2.0
assay (LLOQ 25 IU/mL)
Safety endpoints■ Frequencies of serious AEs, discontinuations due to AEs, grade 3/4 AEs, and laboratory
abnormalities3
Week
0 4 8 12 16 20 24 28 32 36 40
DCV + SOF + RBV12 weeks 24-week follow-up
24-week follow-upDCV + SOF + RBV16 weeks
1:1 randomization(N = 50)
N = 50DCV 60 mg dailySOF 400 mg dailyRBV (weight-based 1200 or 1000 mg/day)
Stratified by fibrosis stage
(F3 or F4)
Inclusion / Exclusion Criteria
4
Key inclusion criteria■ Adults (≥ 18 years) with HCV GT 3 infection
■ HCV treatment-naive or -experienced– Excluding patients with prior exposure to NS5A inhibitors
■ Advanced fibrosis (F3) or compensated cirrhosis (F4)– Assessed by liver biopsy > FibroScan (advanced fibrosis: 9.6 to < 14.6 kPa;
cirrhosis: 14.6 kPa) > FibroTest + APRI above 2
Key exclusion criteria■ Evidence of hepatic decompensation
– Albumin < 35 g/L and platelets < 50 x 109 cells/L
■ Pregnancy or not using contraception
ALLY-3+
Baseline Demographics and Disease CharacteristicsALLY-3+
DCV+SOF+RBVOverallN = 50
DCV+SOF+RBV12 Weeks
N = 24
DCV+SOF+RBV16 Weeks
N = 26Age, median (range) yrs 53.5 (36–73) 53.0 (36–73) 56.0 (42–62)Male, n (%) 40 (80) 18 (75) 22 (85)Race, n (%)
WhiteAsian
49 (98)1 (2)
23 (96)1 (4)
26 (100)0
IL28B non-CC, n (%) 28 (56) 13 (54) 15 (58)HCV RNA, median (range) log10 IU/mL 6.87 (4.6–7.8) 6.70 (4.6–7.6) 6.91 (4.7–7.8)
HCV RNA category (IU/mL), n (%) 2 million 6 million
38 (76)26 (52)
18 (75)11 (46)
20 (77)15 (58)
Fibrosis stage, n (%) Advanced fibrosis (F3) Cirrhosis (F4)
14 (28)36 (72)
6 (25)18 (75)
8 (31)18 (69)
Albumin, median (range) g/L 43 (33–48) 43.0 (33–47) 42.5 (34–48)Platelets, median (range) 109 cells/L 161 (63–324) 161 (63–299) 155 (84–324)Prior HCV treatment experience, n (%)
Naive 13 (26) 6 (25) 7 (27) Experienceda 37 (74) 18 (75) 19 (73) IFN-based regimens 31 (62) 15 (63) 16 (62) SOF-based regimensb 6 (12) 3 (13) 3 (12)
a Includes 30 patients with cirrhosis (F4); 7 patients with advanced fibrosis (F3); b Includes 5 patients (12-week, n = 2; 16-week, n = 3) who relapsed after a previous SOF + RBV regimen, and 1 patient (12-week) who relapsed after SOF + IFN/RBV. 5
SVR12: All Treated Patients
VBTa 0 0 0
Relapseb 4 2 2
Deathc 1 1 0
ALLY-3+
0102030405060708090
100
Overall 12 Weeks 16 Weeks
HCV
RN
A <
LLO
QTD
/TN
D (%
)
90 88 92
4550
2124
2426
ITT ANALYSIS (Primary Endpoint)
6
a VBT (virologic breakthrough}: confirmed HCV RNA 1 log10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment.
SVR12: All Treated Patients
a VBT (virologic breakthrough}: confirmed HCV RNA 1 log10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment.
VBTa 0 0 0
Relapseb 4 2 2
Deathc 1 1 0
ALLY-3+
VBTa 0 0 0
Relapseb 4 2 2
0102030405060708090
100
Overall 12 Weeks 16 Weeks
HCV
RN
A <
LLO
QTD
/TN
D (%
)
90 88 92
4550
2124
2426
ITT ANALYSIS (Primary Endpoint)
0102030405060708090
10092
Overall 12 Weeks 16 Weeks
91 92
4549
2426
2123
HCV
RN
A <
LLO
QTD
/TN
D (%
)
OBSERVED ANALYSIS
7
SVR12: Patients with Advanced Fibrosisa
ALLY-3+
100 100 100
0102030405060708090
100
Overall 12 Weeks 16 Weeks
1414
66
88
HCV
RN
A <
LLO
QTD
/TN
D (%
)
8a Diagnosed by FibroScan 9.6 to < 12.5 kPa (n = 9), FibroScan ≥ 12.5 – 14.6 kPa (n = 4), liver biopsy, (n = 1).
SVR12: Patients with CirrhosisALLY-3+
ITT ANALYSIS
VBTa 0 0 0Relapseb 4 2 2Deathc 1 1 0
0102030405060708090
100
1518
1618
86 83 89
Overall 12 Weeks 16 Weeks
HCV
RN
A <
LLO
QTD
/TN
D (%
)
3136
9
a VBT (virologic breakthrough): confirmed HCV RNA 1 log10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment; cirrhosis status diagnosed by liver biopsy (F4) n = 9; FibroScan ≥ 14.6, n = 27.
SVR12: Patients with CirrhosisALLY-3+
ITT ANALYSIS
VBTa 0 0 0Relapseb 4 2 2Deathc 1 1 0
VBT 0 0 0
Relapse 4 2 2
OBSERVED ANALYSIS
0102030405060708090
10089 88 89
1618
Overall 12 Weeks 16 WeeksH
CV R
NA
< LL
OQ
TD/T
ND (
%)
3135
1517
0102030405060708090
100
1518
1618
86 83 89
Overall 12 Weeks 16 Weeks
HCV
RN
A <
LLO
QTD
/TN
D (%
)
3136
10
a VBT (virologic breakthrough): confirmed HCV RNA 1 log10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment; cirrhosis status diagnosed by liver biopsy (F4) n = 9; FibroScan ≥ 14.6, n = 27.
SVR12 (ITT) by Prior TreatmentALLY-3+
11
11
44
2022
2022
HCV
RN
A <
LLO
QTD
/TN
D (%
)
Overall 12 Weeks 16 Weeks0
102030405060708090
100 87 88 86
2630
1416
1214
2630
1416
2630
1416
TREATMENT-EXPERIENCEDCirrhotic Patients
Naive Experienced0
102030405060708090
100
HCV
RN
A <
LLO
QTD
/TN
D (%
)
TREATMENT HISTORYAll Patients
1213
3337
92 89
Baseline Characteristics of Patients Experiencing Relapse
Patient TreatmentGroup
Prior Treatment
IL28B Genotype
HCV RNA(log10
IU/mL)
FibroScan(kPa)
Albumin(g/L)
Platelets( 109/L)
1(51/M)
12wks None CC 6.7 66.5 33 83
2(53/M)
12wks
IFN-based (VBT) CT 7.0 19.0 43 157
3(61/M)
16wks
SOF + RBV(relapse) CT 5.3 NA
(biopsy) 41 188
4(57/M)
16wks
SOF + RBV(relapse) CT 6.8 14.6 46 201
ALLY-3+
VBT, virologic breakthrough;No patients had RBV dose reductions.
■ All patients had cirrhosis
13
Resistance-associatedVariants (RAVs) at Baseline and Failure
■ At failure, all 4 patients who relapsed had NS5A-Y93H■ No SOF-associated RAVs in NS5B were observed at baseline or relapse (sensitivity 1%)
– S282T or any substitution at L159, L320, or V321
Resistance assessed by population sequencing (sensitivity ≥ 10%)Assessment of baseline RAVs on SVR12 excludes 1 patient without RAVs who died of dilated cardiomyopathy on Day 72, unrelated to treatment. One relapse without A30K or Y93H had baseline M28I polymorphism not present at failure. M28I does not affect DCV susceptibility in vitro.
4550
No BL NS5A RAVs
n = 41
BL NS5A RAVsn = 8
Relapse
SVR1288% (7/8)
A30K(n = 5)
A30A/K(n = 1)
Y93H (n = 1)
Y93Y/H (n = 1)
SVR1293%
(38/41)
14
On-Treatment Safety Summary
AE, adverse event; ULN, upper limit of normal.a No serious AE was related to treatment. 12-week: dilated cardiomyopathy (n = 1) and somnolence (n = 1); 16-week: pneumonia (n = 1), arteriosclerosis (n = 1), and basal cell carcinoma (n = 1); b Not related to treatment (dilated cardiomyopathy on Day 72).c All listed events were of grade 3 intensity. No grade 4 laboratory abnormalities.
ALLY-3+
n (%)
DCV + SOF + RBVOverallN = 50
DCV + SOF + RBV
12 weeksN = 24
DCV + SOF + RBV
16 weeksN = 26
Any AE 47 (94) 23 (96) 24 (92)
Serious AEsa 5 (10) 2 (8) 3 (12)
Deathsb 1 (2) 1 (4) 0
Discontinuations for AEs 0 0 0
Grade 3–4 AEs 4 (8) 2 (8) 2 (8)
RBV dose reduction 6 (12) 2 (8) 4 (15)
Treatment-emergent grade 3–4 laboratory abnormalitiesc
Hemoglobin < 9.0 g/dL or decrease ≥ 4.5 g/dL 1 (2) 0 1 (4) Total bilirubin 2.5 x ULN 2 (4) 1 (4) 1 (4) Platelet count < 50 x 109/L 0 0 0 ALT 5 x ULN 0 0 0 AST > 5 x ULN 0 0 0 Creatinine > 1.9 x ULN 0 0 0
14
Common AEs on Treatment ( 10% Overall)
Grades 1–4 regardless of causality.
ALLY-3+
15
n (%)
DCV + SOF + RBVOverall N = 50
DCV + SOF + RBV 12 weeks
N = 24
DCV + SOF + RBV 16 weeks
N = 26
Insomnia 15 (30) 8 (33) 7 (27)
Fatigue 13 (26) 6 (25) 7 (27)
Headache 12 (24) 7 (29) 5 (19)
Irritability 7 (14) 5 (21) 2 (8)
Asthenia 7 (14) 2 (8) 5 (19)
Diarrhea 5 (10) 1 (4) 4 (15)
Dyspnea 5 (10) 2 (8) 3 (12)
Summary & ConclusionsALLY-3+
■ Overall, 90% SVR12 was achieved in HCV GT 3-infected patients with advanced fibrosis or compensated cirrhosis treated with DCV + SOF + RBV – SVR12 was comparable for the 12-week (88%) and 16-week (92%) groups– No on-treatment virologic failures; two relapses in each treatment arm
■ 100% SVR12 among patients with advanced fibrosis
■ 86% SVR12 among patients with cirrhosis (mostly treatment experienced)
■ Treatment was safe and well tolerated; no patient discontinued for AEs
■ DCV + SOF + RBV for 12 or 16 weeks is a highly efficacious therapy for GT 3-infected patients with advanced fibrosis or compensated cirrhosis, a population in urgent need of treatment
16
■ The authors thank the patients and their families for their support and dedication, and investigators and research staff at all study sites
■ The authors acknowledge Bristol-Myers Squibb personnel: Kimberly Brown, Patricia Mendez, and Eric Y Wong
■ Editorial support was provided by Nick Fitch of Articulate Science and funded by Bristol-Myers Squibb
■ ClinicalTrials.gov registration number NCT02319031 (Study AI444326)
Acknowledgments
18
ALLY-3+
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