Daclatasvir and Sofosbuvir in Patients with Recurrent HCV Following Liver Transplantation with Advanced Fibrosis or Cirrhosis: United States Multicenter Treatment Protocol Kwo P, 1 Fried MW, 2 Reddy R, 3 Soldevila-Pico C, 4 Khemichian S, 5 Darling J, 2 Napoli A, 6 Anduze-Faris B, 6 Brown RS Jr 7 1 Indiana University, Indianapolis, IN; 2 University of North Carolina, Chapel Hill, NC; 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA; 4 Department of Medicine, University of Florida, Gainesville, FL; 5 Keck School of Medicine, University of Southern California, Los Angeles, CA; 6 Bristol-Myers Squibb, Plainsboro, NJ; 7 Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY The Liver Meeting 2015® San Francisco, CA, 13–17 November 2015
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Daclatasvir and Sofosbuvir in Patients with Recurrent HCV Following Liver Transplantation with Advanced Fibrosis or Cirrhosis: United States Multicenter.
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Daclatasvir and Sofosbuvir in Patients withRecurrent HCV Following Liver Transplantation
with Advanced Fibrosis or Cirrhosis:United States Multicenter Treatment Protocol
Kwo P,1 Fried MW,2 Reddy R,3 Soldevila-Pico C,4 Khemichian S,5 Darling J,2 Napoli A,6 Anduze-Faris B,6 Brown RS Jr7
1Indiana University, Indianapolis, IN; 2University of North Carolina, Chapel Hill, NC; 3Department of Medicine, University of Pennsylvania, Philadelphia, PA; 4Department of Medicine, University of
Florida, Gainesville, FL; 5Keck School of Medicine, University of Southern California, Los Angeles, CA; 6Bristol-Myers Squibb, Plainsboro, NJ;7Department of Medicine, Columbia University College of
Physicians & Surgeons, New York, NY
The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015
Background
■ There are no FDA-approved all-oral regimens in the US for the treatment of post-liver transplant (LT) HCV recurrence with F3 fibrosis or F4 cirrhosis
■ Phase 3 data (ALLY-1)1 demonstrated high rates of SVR12 (94%) in LT recipients with HCV recurrence following 12 weeks of treatment with daclatasvir (DCV) + sofosbuvir (SOF) + ribavirin (RBV)– DCV + SOF has pangenotypic anti-HCV activity in vitro
■ Globally, DCV has been provided to ≈ 7000 patients with advanced disease, and without approved treatment options, in early access / compassionate use programs
■ We present interim findings from a US Expanded Access Protocol in LT recipients with recurrent HCV infection and advanced fibrosis/cirrhosis or fibrosing cholestatic hepatitis (FCH)– Analyses include 58 patients who have enrolled and initiated treatment
Poordad F, et al. EASL 2015. Abstract L08.
U.S. Expanded Access Program
■ Objective:
– Provide DCV to be administered with SOF for 24 weeks to patients without approved treatment options and life expectancy < 12 months
■ Methodology:
– Open-label, multicenter protocol conducted in partnership with the HCV-TARGET consortium
– Allows for rapid enrollment through established HCV-TARGET consortiumsites
– Comprehensive efficacy/safety data collection and analysis
US EAP Site Locations With Enrolled Patients
U.S. Expanded Access Protocol Design
a Cohort added by protocol amendment (Nov 2014); treatment is ongoing, data to be presented at later date.b HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12.
Post-transplant withadvanced fibrosis/ cirrhosis (F3/4) or FCH
Decompensated cirrhosis(Child-Pugh C)a
DCV 60 mg QD +SOF 400 mg QD
Week 0 Week 36Primary endpoint: SVR12b
Week 48
DCV 60 mg QD +SOF 400 mg QD
Week 24
Follow-up
Post-transplant cohort inclusion criteria
■ Liver transplant recipients with post-transplant HCV recurrence (any genotype) and advanced fibrosis (F3/4) or FCH
■ Creatinine clearance > 30 mL/min■ Treatment naive or experienced– RBV could be added at physician’s discretion following consult with BMS medical monitor
Demographic and Baseline Disease CharacteristicsPost-transplant Cohort
ParameterDCV + SOF
N = 55DCV + SOF + RBV
N = 3All Patients
N = 58Age, median [range] years 61 [34–79] 62 [60–63] 61 [34–79] Male, n (%) 41 (75) 3 (100) 44 (76) Race, n (%)
White 47 (86) 2 (67) 49 (85) Black / African American 5 (9) 1 (33) 6 (10) Other 3 (6) 0 3 (5)
HCV RNA, mean log10 IU/mL 6.83 6.45 6.82HCV genotype, n (%)
a MELD score frequency denominators based on number of patients with cirrhosis.MMF, mycophenolate mofetil; MPA, mycophenolic acid.
Patient DispositionPost-transplant Cohort
a Related to incomplete SOF access: 1 patient received SOF+DCV for 4 days in hospital; 1 patient received DCV+SOF for 12 weeks (achieved SVR).
Treatment Outcome Availablen = 34
Started TreatmentN = 58
Ongoing Treatmentn = 14 (24%)
Ended Treatmentn = 44 (76%)
Completed Treatmentn = 36 (62%)
Discontinued Prematurelyn = 8 (14%)
Adverse event (n = 4)Death (n = 2)Othera (n = 2)
Treatment Outcome Pendingn = 10
Interim SVR12 ResultsPost-transplant Cohort
HCV genotype
DCV + SOF DCV + SOF + RBV All patients
GT 1 GT 3 All GT0
20
40
60
80
10089
10089
100 10091 91
SVR
12, %
2427
11
2528
66
3033
11
3134
Interim SVR12 ResultsPost-transplant Cohort
DCV + SOF DCV + SOF + RBV All patients
GT 1 GT 3 All GT0
20
40
60
80
10089
10089
100 10091 91
SVR
12, %
11
2528
66
3033
11
3134
2427
Relapse, n=1Deaths, n=2
■ NS5A sequencing (population-based) in relapse patient identified Y93S RAV
HCV genotype
Patients with Fibrosing Cholestatic HepatitisPost-transplant Cohort
■ Among the 58 enrolled patients, 7 had FCH, of whom 4 have data at post-treatment Week 12– All 4 showed rapid viral decline and achieved SVR12– General improvements from baseline in MELD score and total bilirubin levels
22
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PatientHCV
Genotype TreatmentWeeks of
TreatmentReason for
DiscontinuationBilirubin Normalized
at EOT SVR121 1 DCV + SOF 24 - Yes Yes2 3 DCV + SOF 17 Headachea Yes Yes3 1a DCV + SOF 12 Insurance denial Yes Yes4 3 DCV + SOF 10 Pruritusa No Yes
a Headache and pruritus considered by investigators as not related to HCV therapy.
FCH Patients with SVR12
Patients with Dual Kidney / Liver TransplantPost-transplant Cohort
■ Among the 58 enrolled patients, 4 had dual kidney / liver transplants– 3 with cirrhosis – All diabetic– All receiving tacrolimus-based
immunosuppression
■ All patients completed 24 weeks of treatment
■ All patients achieved SVR12
Patients with Dual Kidney/Liver Transplant
ParameterDCV + SOF
N = 4Age, median (range) years 68.5 (61–79) Male, n (%) 4 (100)Race, n (%)
White 3 (75)Black / African American 1 (25)
HCV genotype, n (%)1 2 (50)3 2 (50)
Cirrhosis, n (%) 3 (75)Diabetes, n (%) 4 (100)Creatinine clearance, median (range) 73.3 (55.5–91.2)
SVR12 4 (100)
SafetyPost-transplant Cohort
■ Most serious AE related to ongoing advanced liver disease– 2 events of acute renal failure in 1 patient considered possibly treatment-related
■ No reports of graft rejection
Parameter, n (%)DCV + SOF
N = 55DCV + SOF + RBV
N = 3All Patients
N = 58Deathsa 2 (4) 0 2 (3)Serious adverse events 15 (27) 0 15 (26)Adverse events leading to discontinuationb 4 (7) 0 4 (7)
aDeaths included 1 renal failure (considered unrelated to program therapy), 1 liver failure.bAEs leading to discontinuation were hemodialysis, headache, pruritus and small intestine obstruction.
■ DCV + SOF ± RBV for 24 weeks achieved high rates of SVR12 in patients with severe recurrent post-transplant HCV infection
– GT 1 infection: 91% (25 of 28)– GT 3 infection: 100% (6 of 6)– FCH: 100% (4 of 4)– Dual liver/kidney transplant: 100% (4 of 4)
■ Therapy was generally safe and well tolerated; no events of graft rejection
■ HCV regimen allowed a broad range of immunosuppressive regimens
■ Program enrollment closed 13 November; final results for post-transplant and decompensated cohorts will be presented at a later date
SummarySummary
Disclosures and Acknowledgments
■ The authors thank the study participants and their families for their support and dedication, and investigators and research staff at all study sites
Investigators:
Hugo Vargas, Joseph Galati, Consuelo Soldevila-Pico, Rajender Reddy, Robert Brown, Raymond Chung, Joseph Lim, Paul Kwo, Stuart Gordon, Shobha Joshi, Jama Darling, Richard Sterling, Paul Gaglio, Arun Jesudian, Saro Khemichian, Jaime Aranda Michel, Devina Bhasin, Philipe Zamor, Isabel Zacharias, Paul Thuluvath
■ The authors thank the HCV-TARGET team and BMS personnel for their support of study execution:
Angie Bauer, Lauren E Morelli, Joy A Peter, Monika Vainorius, Candace Mankowski, Susan Hannah
■ Andrew Napoli and Beatrice Anduze-Faris are employees of Bristol-Myers Squibb
■ Editorial assistance was provided by A Stead of Articulate Science with funding from Bristol-Myers Squibb