Safety and Efficacy of Daclatasvir Plus Sofosbuvir With or Without Ribavirin for the

Treatment of Chronic HCV Genotype 3 Infection: Interim Results of a Multicenter

European Compassionate Use Program

Welzel TM,1 Petersen J,2 Ferenci P,3 Gschwantler M,4 Herzer K,5 Cornberg M,6 Schott E,7 Berg T,8 Spengler U,9 Weiland O,10 van der Valk M,11 Geier A,12

Rockstroh JK,9 Peck-Radosavljevic M,3 Zhao Y,13 Jimenez-Exposito MJ,14 Zeuzem S1

1Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany; 2IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany; 3Medizinische Universität Wien, Vienna, Austria; 4Wilhelminenspital, Vienna, Austria;

5Universitätsklinikum Essen (AöR), Essen, Germany; 6Medizinische Hochschule Hannover, Hannover, Germany; 7Charité Universitätmedizin Berlin, Berlin, Germany; 8Universitätsklinikum Leipzig, Leipzig, Germany; 9Universitätsklinikum

Bonn, Bonn, Germany; 10Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; 11Academic Medical Center, Amsterdam, Netherlands; 12Universitätsklinikum Würzburg, Würzburg, Germany; 13Bristol-Myers Squibb,

Hopewell, NJ, USA; 14Bristol-Myers Squibb, Princeton, NJ, USA

The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015 Mercury-Nr: 1392DE15NP07880-03

Date of preparation: Nov-2015

2

Background

■ Treatment of HCV genotype (GT) 3-infected patients is a challenge, with urgent need of effective antiviral therapies1

■ The pan-genotypic, 12-week, all-oral, RBV-free regimen of DCV and SOF achieved 96% SVR12 rates in GT 3-infected noncirrhotic patients (ALLY-3)2

■ Optimized treatment for GT 3-infected patients with advanced liver disease remains a medical need

■ Here we report interim findings on the combination of DCV + SOF RBV in HCV GT 3-infected patients with advanced liver disease enrolled in the European DCV compassionate use program (CUP; AI444-237)3

RBV, ribavirin; DCV, daclatasvir (NS5A inhibitor); SOF, sofosbuvir, (NS5B inhibitor); DAA, direct-acting antiviral.1. Pol S, et al. Liver Intl 2014;34:(18–23); 2. Nelson D, et al. Hepatology; 2015;61(4):1127–1135; 3. EU CUP, AI444-237; ClinicalTrials.gov

identifier 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)

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All Treated GT 3-Infected Patients

N = 102

Efficacy PopulationN = 82

Excluded from this interim analysis, N = 20a

■ Did not reach posttreatment Week 12, n = 7 ■ Missing data (not caused by death or

treatment discontinuation due to AE), n = 13

Safety PopulationN = 102

Populations and Statistical Analysis(Interim Analysis)

■ Primary Efficacy Analysis (mITT): – Patients with missing data who died, discontinued treatment due to AEs, or had

virologic breakthrough/relapse before posttreatment Week 12 were classified as failures

■ Safety Analysis: – Clinical (AEs, serious AEs, AEs leading to discontinuation, and deaths) and laboratory

abnormalities

a All patients had HCV RNA < LLOQ, TD or TND, at EOT (Week 24) or at the last available assessment.

All Treated PatientsN = 485

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Demographics and Baseline Characteristics

ParameterDCV + SOF

N = 62DCV + SOF + RBV

N = 40All Patients

N = 102Age, median (range) yr 54.5 (33–75) 55 (31–62) 55 (31–75)Male, n (%) 41 (66) 28 (70) 69 (68)White, n (%) 56 (90) 34 (85) 90 (88)HCV RNA log10 IU/mL, median (range)a 5.4 (0–6.9) 6.0 (0–7.1) 5.6 (0–7.1)

HCV RNA ≥ 2,000,000 IU/mL, n (%)a 8 (13) 13 (33) 21 (21)Cirrhosis, n (%)b 51 (82) 36 (90) 87 (85)

Child-Pugh class, n (%)a,c

A 23 (45) 18 (50) 41 (47)B 18 (35) 16 (44) 34 (39)C 9 (18) 2 (6) 11 (13)

MELD score median (range)a 10.0 (6–20) 11.0 (6–22) 10.0 (6–22)MELD score > 15, n (%)a,c 6 (12) 3 (8) 9 (10)

ALT, median (range) IU/La 52 (15–372) 59 (19–211) 56 (15–372)Total bilirubin, median (range) mmol/L 21 (5–99) 26 (7–74) 22 (5–99)Albumin, median (range) g/La 35 (18–50) 34 (22–50) 34 (18–50)Platelet count, median (range) × 109/La 86 (23–378) 75 (32–273) 75 (23–378)Prior HCV therapy, n (%) 34 (55) 26 (65) 60 (59)Liver transplant recipient, n (%) 4 (6) 4 (10) 8 (8)HIV coinfection, n (%)a 9 (15) 6 (15) 15 (15)HBV coinfection, n (%)a 4 (6) 1 (3) 5 (5)a Excludes patients with missing data; b Cirrhosis diagnosed by liver biopsy (Metavir > F3, Ishak > 4, or the equivalent), n=9; FibroScan

(> 14.6 kPa), n=48; or FIB-4 score (> 3.25), n=30. Cirrhosis status indeterminate/not reported, n=8: DCV + SOF, n=5; DCV + SOF + RBV, n=3;c Percentages based on cirrhotic patients.

0

20

40

60

80

100 86 88 87

Primary Efficacy Analysis – SVR12 (mITT)

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Not Achieving SVR12 7 4 11Breakthrough 1 0 1Relapse 3 3 6Discontinuation (AE) 0 1 1Deatha 3 0 3

4249

7182

2933

DCV + SOF

DCV + SOF + RBV

All Patients

Breakthrough: confirmed on-treatment HCV RNA ≥ 1 log10 IU/mL over nadir, or ≥ LLOQ if previously < LLOQ, TD or TND; Relapse: confirmed HCV RNA ≥ LLOQ during any posttreatment visit following HCV RNA < LLOQ, TD or TND, at end-of-treatment;a Includes 1 patient who died during follow-up period; HCV RNA < LLOQ at post-treatment Week 10.

HCV

RN

A <

LLO

Q, T

D o

r TN

D%

± 9

5% C

I

Cirrhosisᵃ A B C < 10 10 to 15 > 150

20

40

60

80

10088

100

8075

100

80 8086 85 86

100

89 88

100

SVR12 (mITT) in Patients With Cirrhosis

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DCV + SOF DCV + SOF + RBV

HCV

RN

A <

LLO

Q, T

D o

r TN

D, %

3742

2529

1919

1215

1214

1620

68

Child-Pugh Class MELD Score Categoryb

1113

22

45

22

1517

89

1717

a Excludes 4 patients with indeterminate cirrhosis status (1 DCV+SOF; 3 DCV+SOF+RBV); all achieved SVR12; cirrhosis was absent in 5 patients (4 DCV+SOF; 1 DCV+SOF+RBV); all except 1 (DCV+SOF) achieved SVR12;

b Excludes 1 cirrhotic patient with missing baseline MELD data; patient discontinued therapy at Week 4 due to AE (non-SVR12).

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SVR12 (mITT) by Subgroup

DCV + SOF DCV + SOF + RBV

< 2 × 10⁶ ≥ 2 × 10⁶ Naive Exp'd 12 wks 24 wks0

20

40

60

80

10083

100 100

8391

82 86 8690 92

100 100 100

8171

92

HCV

RN

A <

LLO

Q, T

D o

r TN

D, %

3542

1820

77

1112

33

44

1921

1212

2328

1721

56

55

HCV RNA, IU/mLa Prior HCV therapy

Duration of treatmentb

67

57

3642

2426

a Excludes 1 patient with missing data at baseline (relapse).b Duration of therapy estimated based on time of exposure to program therapy: 6 patients initiated SOF + RBV before adding DCV;

12 week arm includes 4 patients who received treatment <10 Weeks (3 D/C due to AEs; 1 death); 1 achieved SVR12.

Liver txp recipients

HIV coinfected

patients

Changes in Liver Disease Parameters From Baseline to Post-Treatment Week 12

10Data indicate median, IQR, range.

ALT

Baseline Follow-up0

25

50

75

100

300400

IU/L

Total Bilirubin

Baseline Follow-up0

25

50

75

100

125

mol

/L

Albumin

Baseline Follow-up0

102030405060

g/L

Platelets

Baseline Follow-up0

100

200

300

400

plat

elet

s ×

109 /L

Albumin Platelets

ALT Total Bilirubin

n = 100 n = 69

n = 87 n = 60

n = 75 n = 56

n = 101 n = 70

On-Treatment Safety Summary

Patients, n (%)DCV + SOF

N = 62DCV + SOF + RBV

N = 40All Patients

N = 102Total AEs 40 (65) 28 (70) 68 (67)Serious AEs 14 (23) 7 (18) 21 (21)

Treatment-related serious AEs 2 (3) 2 (5) 4 (4)AEs leading to discontinuation or death 3 (5) 3 (8) 6 (6)

Death 2 (3) 0 2 (2)Most frequent AEs (≥5% of patients)

Fatigue 8 (13) 4 (10) 12 (12)Nausea 4 (6) 6 (15) 10 (10)Anemia 2 (3) 11 (28) 13 (13)

Treatment-emergent grade 3 or 4 laboratory abnormalities

Hemoglobin < 90 g/L 3 (5) 4 (11) 7 (7)ALT > 5 × ULN 0 0 0AST > 5 × ULN 0 0 0Total bilirubin > 2.5 × ULN 1 (2) 4 (15) 5 (7)Creatinine > 1.8 × ULN 0 0 0

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On-Treatment Safety Summary

Patients, n (%)DCV + SOF

N = 62DCV + SOF + RBV

N = 40All Patients

N = 102Treatment-emergent serious AEs

Pancytopenia 1 (2) 1 (1)Hepatocellular carcinoma 1 (3) 1 (1)Hepatic encephalopathy 1 (2) 1 (1)Circulatory collapse 1 (3) 1 (1)

AEs leading to discontinuation or deatha

Multiorgan failureb 2 (3) 0 2b (2)General physical health deterioration 1 (3) 1 (1)Pneumonia 1 (2) 1 (1)Hepatic encephalopathy 1 (2) 1c (1)Dyspnea 1 (3) 1c (1)Circulatory collapse 1 (3) 1c (1)

a Includes more than 1 event in some patients.b Deaths: multiorgan failure/pneumonia (n=1), multiorgan failure/liver failure (n=1); none were considered treatment-related.c Reported as treatment-related.

Summary and Conclusion

■ In a real-life clinical setting, DCV + SOF ± RBV achieved high SVR rates (87%) in HCV GT 3–infected patients at high risk of hepatic decompensation or death – 87% SVR12 in cirrhotic patients (including decompensated cirrhosis)

– Comparable SVR12 rates with or without RBV in the regimen

■ Improvements in liver function were observed

■ DCV + SOF ± RBV was generally safe and well tolerated

– Few discontinuations due to AEs, treatment-related serious AEs, or grade 3/4 laboratory abnormalities

■ These findings suggest that DCV + SOF RBV is an effective and well tolerated oral treatment for patients with GT 3 infection, including those with most advanced disease

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Acknowledgments

■ The authors thank the patients and their families, and physicians and research staff at all program sites

■ Editorial support was provided by J Bergen of Articulate Science and was funded by Bristol-Myers Squibb

■ ClinicalTrials.gov registration number NCT02097966

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14

Characteristics of Patients With Virologic Failure

Baseline Characteristicsa

Pt

Reason for VirologicFailure

Prior HCVTherapy

HCV RNA (log10 IU/mL)

Fibrosis Stage/

Cirrhosis

Child-Pugh Class

MELD Score

Treatment Regimen

Therapy Duration

(Weeks)

1 Relapse Experienced 5.2 F3 - - DCV+SOF 24

2 Relapse Experienced 5.6 - - - DCV+SOF 24

3 Relapse Experienced - Cirrhosis A 9 DCV+SOF+RBV 24

4 Relapse Experienced 6.0 Cirrhosis A 13 DCV+SOF+RBV 7b

5 Relapse Experienced 5.4 Cirrhosis B 11 DCV+SOF 24

6 Relapse Experienced 6.6 Cirrhosis B 11 DCV+SOF+RBV 24

7 Virologic breakthroughc Experienced 5.7 Cirrhosis B 12 DCV+SOF 24

a No patients were HIV/HCV coinfected or liver transplant recipients; b Discontinuation due to AE at Week 7; HCV RNA > LLOQ at posttreatment Week 12;c Patient never undetectable during treatment.