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+