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 (%)

1 39 (71) 2 (67) 41 (71) 2 2 (4) 0 2 (3)3 14 (26) 1 (33) 15 (26)

Weeks since liver transplant, median [range] 288 [3–959] 309 [40–412] 299 [3–959]Dual kidney / liver transplant, n (%) 4 (7) 0 4 (7)HCV treatment experienced, n (%) 31 (56) 3 (100) 34 (59)Pre-transplant hepatocellular carcinoma, n (%) 16 (29) 2 (67) 18 (31)Post-transplant decompensating event, n (%) 39 (71) 3 (100) 42 (72)Post-transplant diabetes, n (%) 23 (42) 2 (67) 25 (43)Fibrosing cholestatic hepatitis, n (%) 7 (13) 0 7 (12)

Baseline Disease CharacteristicsPost-transplant Cohort

ParameterDCV + SOF

N = 55DCV + SOF + RBV

N = 3All Patients

N = 58Cirrhosis, n (%) 43 (78) 2 (67) 45 (78)MELD score, n (%)a

≤ 9 15 (27) 1 (33) 16 (28) 10–15 9 (16) 1 (33) 10 (17) ≥ 16 3 (6) 0 3 (5)

Pending 16 (29) 0 16 (28)Albumin, median [range] g/dL 3.4 [1.7–4.7] 3.7 [2.6–4.6] 3.4 [1.7–4.7]Total bilirubin, median [range] mg/dL 0.9 [0.3–15.3] 0.9 [0.4–1.5] 0.9 [0.3–15.3]Creatinine, median [range] g/dL 1.2 [0.7–2.1] 1.0 [0.9–1.2] 1.2 [0.7–2.1]INR, median [range] 1.1 [1.0–1.5] 1.1 [1.1–1.1] 1.1 [1.0–1.5]Platelets, median [range] × 103 cells/µL 117 [41–258] 199 [101–234] 119 [41–258]Immunosuppressant use

Tacrolimus 37 (67) 2 (67) 39 (67) Cyclosporine 13 (24) 1 (33) 14 (24) Everolimus / sirolimus 6 (11) 0 6 (10)MMF / MPA 20 (36) 2 (67) 22 (38)Steroid use 5 (9) 0 5 (9)

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

22

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)

Adverse events, > 10% patients Fatigue 15 (27) 2 (67) 17 (29) Nausea 14 (25) 2 (67) 16 (28) Diarrhea 8 (15) 1 (33) 9 (16)

Asthenia 7 (13) 0 7 (12) Upper respiratory tract infection 6 (11) 0 6 (10)

Arthralgia 5 (9) 1 (33) 6 (10)

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

Serious Adverse Events

15

Event

Patients with SAE, n (%) SAE, n

All serious AE 15 (26) Hepatic encephalopathy 5 (9) 8Renal failure acute 3 (5) 6Small intestinal obstruction 1 (2) 2Hypervolemia 2 (3) 2Calculus urinary 1 (2) 1Cholangitis 1 (2) 1Death not specified 1 (2) 1Depression 1 (2) 1Diarrhea 1 (2) 1Fluid overload 1 (2) 1Gastroenteritis viral 1 (2) 1Generalized edema 1 (2) 1Hemangioma 1 (2) 1Hair follicle tumor benign 1 (2) 1Hepatic enzyme increased 1 (2) 1Hepatic failure 1 (2) 1

Event

Patients with SAE, n (%) SAE, n

Hyperglycemia 1 (2) 1Hyponatremia 1 (2) 1Incisional drainage 1 (2) 1Mental status changes 1 (2) 1Edema peripheral 1 (2) 1

Esophageal varices hemorrhage 1 (2) 1Pyrexia 1 (2) 1Renal failure 1 (2) 1Squamous cell carcinoma 1 (2) 1Subarachnoid hemorrhage 1 (2) 1Syncope 1 (2) 1

Upper respiratory tract infection 1 (2) 1

All Serious Adverse Events in the Post-Transplant Cohort (N = 58)