Daclatasvir in Combination With Sofosbuvir With Or Without Ribavirin Is Safe and Efficacious in...
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Daclatasvir in Combination With Sofosbuvir With Or Without Ribavirin Is Safe and Efficacious in Liver Transplant Recipients With HCV Recurrence:
Interim Results of a European Multicenter Compassionate Use Program
Herzer K,1 Welzel TM,2 Ferenci P,3 Petersen J,4 Gschwantler M,5 Cornberg M,6 Berg T,7 Spengler U,8 Weiland O,9 Van der Valk M,10 Klinker H,11 Rockstroh J,8
Schott E,12 Peck-Radosavljevic M,3 Zhou Y,13 Jimenez-Exposito MJ,13 Zeuzem S2
1Universitätsklinikum Essen (AöR), Essen, Germany; 2Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany; 3Medizinische Universität Wien, Vienna, Austria; 4IFI Institut für Interdisziplinäre
Medizin, Hamburg, Germany; 5Wilhelminenspital, Vienna, Austria; 6Medizinische Hochschule Hannover, Hannover, Germany; 7Universitätsklinikum Leipzig, Leipzig, Germany; 8Universitätsklinikum Bonn, Bonn, Germany; 9Karolinska
University Hospital, Karolinska Institutet, Stockholm, Sweden; 10Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 11Universitätsklinikum Würzburg, Würzburg, Germany; 12Charité
Universitätmedizin Berlin; Berlin, Germany; 13Bristol-Myers Squibb, Princeton, NJ, USA.
The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015
■ Recurrence of HCV infection after liver transplantation is common and a significant threat to graft and patient survival1
■ Interferon-free oral therapies are well tolerated and can achieve high SVR rates with shorter treatment durations and minimal drug-drug interactions
■ The pan-genotypic combination of DCV + SOF + RBV has shown high SVR12 rates (GT 1, 95%; GT 3, 91%) and good tolerability in patients with post-liver transplant HCV recurrence after 12 weeks of therapy (ALLY-1 study)2
■ A European compassionate use program (CUP) provided access to DCV before market authorization to patients in urgent need of treatment
■ Here we report findings on DCV + SOF RBV in liver transplant recipients with HCV recurrence enrolled in the European CUP (AI444-237)3
2
Background
RBV, ribavirin; DCV, daclatasvir (NS5A inhibitor); SOF, sofosbuvir (NS5B inhibitor)1. Narang, et al. Liver Transpl 2010; 16:1228–1235; 2. Poordad, et al. EASL, 50th ICL 2015. Abstract L08; 3. Clinical trials.gov, https://clinicaltrials.gov/ct2/show/NCT02097966.
European DCV Compassionate Use Program
Inclusion criteria■ Age ≥ 18 years with no treatment options ■ High risk of hepatic decompensation or
death within 12 months if left untreated– Or urgent need of viral clearance
(extrahepatic manifestations/comorbidities)
Exclusion criteria■ Creatinine clearance ≤ 30 mL/min■ Pregnancy or not using contraception
Primary objective: To provide access to DCV to patients with life-threatening chronic HCV infection who have no other treatment options
3
Week 24# Week 36Day 1
DCV (60 mg)* + SOF (400 mg) ± RBV† Follow-Up
SVR12‡
Primary endpoint
Additional Optional Follow-Up
Week 48 Week 72
SVR24
#Addition of RBV and shorter duration of treatment at the discretion of the physician
*Dose adjusted for concomitant ARVs‡HCV RNA < LLOQ, TD or TND at post treatment Week 12 (next value carried backward approach)
4
All Treated Liver Transplant Patients with HCV recurrence
N = 87
Efficacy PopulationN = 80
Excluded from this interim analysis, N = 7a
■ Did not reach post-treatment Week 12, n = 3; ■ Informed consent withdrawal, n = 1■ Missing data (not caused by death or
treatment discontinuation due to AE), n = 3
Safety PopulationN = 87
Populations and Statistical Analysis
■ Primary Efficacy Analysis (mITT): – HCV RNA < LLOQ, TD or TND at post-treatment Week 12 (next value carried backward)
– Patients with missing data who died, discontinued treatment due to AEs, or had virologic breakthrough / relapse before post-treatment Week 12 were classified as failures
■ Safety Analysis: – Clinical (AE, serious AE, AE leading to discontinuation and death) and laboratory
abnormalitiesaAll excluded patients had HCV RNA < LLOQ TD or TND at EOT (Week 24) or at the last available assessment (On-treatment Week 12).
All Treated PatientsN = 485
ParameterDCV + SOF
N = 62DCV + SOF + RBV
N = 25All Patients
N = 87Age, median (range) yr 58 (40–75) 58 (39–74) 58 (39–75)Male, n (%) 46 (74) 15 (60) 61 (70)White, n (%)a 59 (95) 22 (88) 81 (93)HCV genotype, n (%) 1a 21 (34) 7 (28) 28 (32) 1b 32 (52) 9 (36) 41 (47) 1 subtype unknown 5 (8) 2 (8) 7 (8) 3 4 (6) 4 (16) 8 (9) 4 0 2 (8) 2 (2) Unknown 0 1 (4) 1 (1)HCV RNA, median (range) log10 IU/mLa 6.3 (0–7.5) 6.2 (0–7.2) 6.2 (0–7.5) HCV RNA ≥ 2,000,000 IU/mL, n (%)a 30 (48) 10 (40) 40 (46)ALT, median (range) IU/La 55 (9–347) 49 (14–235) 53 (9–347)Albumin, median (range) g/La 41 (20–49) 41 (24–47) 41 (20–49)Prior HCV therapy, n (%) 41 (66) 19 (76) 60 (69)HBV coinfection, n (%) 3 (5) 2 (8) 5 (6)a Excludes patients with missing data.
5
Demographic and Baseline Disease Characteristics
6
Baseline Disease Characteristics
ParameterDCV + SOF
N = 62DCV + SOF + RBV
N = 25All Patients
N = 87Time since LT, median (range) years 3.9 (0.3–21.5) 2.2 (0.3–9.1) 3.4 (0.3–21.5)Cirrhosis, n (%)a 24 (39) 13 (52) 37 (43)
Child-Pugh class, n (%)b
A 12 (50) 9 (69) 21 (57) B 8 (33) 4 (31) 12 (32)
C 4 (17) 0 4 (11)MELD score, median (range) 10 (6–25) 10 (6–18) 10 (6–25)MELD score > 15, n (%)b 7 (29) 1 (8) 8 (22)
Fibrosing cholestatic hepatitis, n (%) 8 (13) 2 (8) 10 (11)Immunosuppressive therapy, n (%)c
Tacrolimus 44 (71) 20 (80) 64 (74) Cyclosporine 15 (24) 3 (12) 18 (21) Everolimus 6 (10) 4 (16) 10 (11)
Sirolimus 2 (3) 0 2 (2) Mycophenolate 30 (48) 14 (56) 44 (51)
Prednisone/prednisolone 11 (18) 3 (12) 14 (16)
a Diagnosed by liver biopsy (Metavir >F3, Ishak >4, or the equivalent), n=2; FibroScan (>14.6 kPa), n=19; or FIB-4 score (>3.25), n=16; b Percentages based on cirrhotic patients; c Excludes patients with missing data.
Primary Efficacy Analysis – SVR12 (mITT)
7
0
20
40
60
80
100 91 93
DCV + SOFDCV + SOF + RBVOverall
5458
2022
7480H
CV R
NA
< LL
OQ
, TD
or T
ND
%
± 9
5% C
I
■ 75 of 80 patients treated for 24 weeks; 72 of these 75 (96%) achieved SVR12
Not Achieving SVR12 4 2 6
Breakthrough or relapse 0 0 0
Discontinuation (AE) 0 1 1
Deathsa 4 1 5
a 3 deaths occurred during post-treatment follow-up.
Primary Efficacy Analysis – SVR12 (mITT)
7
0
20
40
60
80
100 91 93
DCV + SOFDCV + SOF + RBVOverall
5458
2022
7480H
CV R
NA
< LL
OQ
, TD
or T
ND
%
± 9
5% C
I
■ 75 of 80 patients treated for 24 weeks; 72 of these 75 (96%) achieved SVR12
Not Achieving SVR12 4 2 6
Breakthrough or relapse 0 0 0
Discontinuation (AE) 0 1 1
Deathsa 4 1 5
a 3 deaths occurred during post-treatment follow-up.
SVR12 (mITT) by HCV Genotype
8
All GT 1ᵃ 1a 1b 3 40
20
40
60
80
100 93 95 94100
94100 100 100 100
1920
77
3032
88
33
44
00
11
HCV genotype b
DCV + SOF DCV + SOF + RBV
HCV
RN
A <
LLO
Q, T
D o
r TN
D, %
5155
1516
aGT 1 subtype unknown in 4 patients: DCV + SOF (n = 3); DCV + SOF + RBV (n = 1); 2 patients achieved SVR12; 1 patient in each arm died.b Excludes 1 patient (DCV + SOF + RBV) with unknown GT; patient discontinued Day 58 due to AE (treatment failure).
Cirrhosisᵃ A B or C ᵇ < 10 ≥ 10 ᶜ FCH0
20
40
60
80
100 9788
100
75
9283
75
100
8288
67
100
60
100
SVR12 (mITT) by Liver Disease Status
9
2124
1212
911
DCV + SOF DCV + SOF + RBV
78
2829
912
1010
23
1112
66
1012
35
Child-Pugh class MELD score
HCV
RN
A <
LLO
Q, T
D o
r TN
D, %
FCH, fibrosing cholestatic hepatitis.a Excludes 6 patients with indeterminate cirrhosis status (5 DCV + SOF; 1 DCV + SOF + RBV); all achieved SVR12.
b 4 patients (DCV + SOF) had Child-Pugh class C; 3 of 4 achieved SVR12.c 5 patients had MELD scores 16–20 (2 of 5 achieved SVR12); 3 patients had MELD scores 21–25 (all SVR12).
68
22
NoCirrhosisa
< 2 × 10⁶ ≥ 2 × 10⁶ 30 – 59 60 – 89 ≥ 900
20
40
60
80
10086
10092
100 100
83
100
86
100 100
SVR12 (mITT) by Baseline Characteristics
9
2529
2828
1012
DCV + SOF DCV + SOF + RBV
99
2426
67
1010
22
1212
22
HCV RNA, IU/mL a Creatinine clearance, mL/min b
HCV
RN
A <
LLO
Q, T
D o
r TN
D, %
a Excludes 2 patients with missing HCV RNA data at baseline.b 3 patients (DCV + SOF) had CrCl < 30 at baseline; 2 of 3 achieved SVR12.
Changes in Liver Disease Parameters From Baseline to Post-Treatment Week 12
11Data indicate median, IQR, range.
ALT
Baseline Follow-up0
255075
100125
300400
IU/m
L
Albumin
Baseline Follow-up0
102030405060
mg/
L
Platelets
Baseline Follow-up0
100
200
300
400
500
plat
elet
s/L
(×10
9 )
Albumin Platelets
ALT
N = 73N = 86
N = 71N = 87N = 57N = 75
g/L
IU/L
plat
elet
s ×
109 /
L
Total Bilirubin
Baseline Follow-up0
25
50
200
300
IU/m
L
Total Bilirubin
N = 69N = 77
mg/
dLm
g/dL
μmol
/L
On-Treatment Safety Summary
Patients, n (%)DCV + SOF
N = 62DCV + SOF + RBV
N = 25All Patients
N = 87Total AEs 34 (55) 17 (68) 51 (59)Serious AEs 10 (16) 6 (24) 16 (18)Treatment-related serious AE 1 (2) 2 (8) 3 (3)
Renal impairment 1 1 2Pancytopenia - 1 1
AEs leading to discontinuation or deatha 4 (7) 4 (16) 8 (9)Deathsb 1 (2) 1 (4) 2 (2)
Sepsis 1 1Spontaneous bacterial peritonitis - 1 1
Graft rejection events 0 0 0Treatment-emergent grade 3 or 4 laboratory abnormalities
Hemoglobin < 90 g/L 5 (8) 5 (20) 10 (11)ALT > 5 × ULN 1 (2) 0 1 (1)AST > 5 × ULN 1 (2) 0 1 (1)Total bilirubin > 2.5 × ULN 1 (2) 1 (5) 2 (3)Creatinine > 1.9 × ULN 5 (8) 0 5 (6)
a Treatment-related events included renal impairment (n=2), seborrheic dermatitis (n=1), and dyspnea (n=1).b All deaths were considered unrelated to program therapy.
10
■ No significant changes in immunosuppressive regimens were required
Summary and Conclusion
■ In a real-world setting, DCV + SOF ± RBV achieved a high SVR12 rate (93%) in 80 liver transplant recipients with recurrent HCV infection– High SVR12 rate regardless of HCV genotype, cirrhosis status or RBV use
– No virologic breakthrough or relapse
■ Median ALT, bilirubin, and albumin levels improved between baseline and post-treatment Week 12
■ DCV + SOF ± RBV was generally safe and well tolerated– Few discontinuations due to adverse events, treatment-related serious AE, or
grade 3 or 4 laboratory abnormalities
■ These results suggest that the pangenotypic, all-oral combination of DCV + SOF + RBV represents an effective and well-tolerated treatment for liver transplant recipients with recurrent HCV, including patients with advanced disease
11
Acknowledgments
■ The authors thank the patients and their families, and physicians and research staff at all program sites
■ Editorial support was provided by R Boehme of Articulate Science and was funded by Bristol-Myers Squibb
■ ClinicalTrials.gov registration number NCT02097966
12