Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection:...

Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection:

Interim Analysis of a French Multicenter Compassionate Use Program

Christophe Hézode,1 Victor De Ledinghen,2 Helene Fontaine,3 Fabien Zoulim,4 Pascal Lebray,5 Nathalie Boyer,6 Dominique Larrey,7 Christine Silvain,8 Danielle Botta-Fridlund,9 Vincent Leroy,10

Marc Bourliere,11 Louis d’Alteroche,12 Isabelle Hubert-Fouchard,13 Dominique Guyader,14 Isabelle Rosa,15 Eric Nguyen-Khac,16 Vincent Di Martino,17 Larysa Fedchuk,18 Raoudha Akremi,18

Yacia Bennai,18 Jean-Pierre Bronowicki,19 on behalf of Bristol-Myers Squibb

1Hépato-gastro-entérologie, CHU Henri-Mondor, Créteil; 2Centre d’Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac; 3Hôpital Cochin, AP-HP, Université Paris-René Descartes, Paris; 4Hôpital de la Croix-Rousse,

Hospices Civils de Lyon, Lyon; 5Service d’Hépatogastroentérologie, Hôpital Pitié Salpêtrière, Paris; 6AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy; 7Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, Montpellier; 8Service d’hépato-gastroentérologie et d’assistance nutritive,

laboratoire inflammation tissus epithéliaux et cytokines EA 4331, CHU Poitiers, Poitiers; 9Hôpital de la Conception, Marseille; 10CHU de Grenoble, Clinique universitaire d’hépato-gastroentérologie, Grenoble; 11Hôpital Saint-Joseph, Marseille; 12CHU Trousseau, Tours;

13Service d’Hépato-Gastroentérologie, CHU Angers, Angers; 14Service des Maladies du Foie, CHU Rennes, Rennes; 15Centre Hospitalier Intercommunal, Créteil; 16Service d’Hépato-gastroentérologie, CHU Amiens Nord, Amiens;

17Service d’Hépatologie et de soins intensifs digestifs, CHRU Jean Minjoz, Besançon; 18Bristol-Myers Squibb Research and Development, Rueil-Malmaison; 19Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France

The Liver Meeting® 2015: The 66th Annual Meeting of the American Association for the Study of Liver Diseases

San Francisco, CA, November 13–17, 2015

Oral 206Corresponding author:

Christophe Hézode ([email protected])

■ Patients infected with HCV genotype (GT) 3 are in urgent need of effective treatments due to the increased risk of accelerated disease progression and hepatocellular carcinoma

■ Daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV) is the only all-oral regimen currently recommended for alla patients with GT 3 infection by EASL1 and AASLD2 treatment guidelines

■ The pangenotypic, 12-week RBV-free regimen of DCV + SOF achieved 96% SVR12 in non-cirrhotic GT 3 patients (ALLY-3)3

■ 12- and 16-week GT 3 data for DCV + SOF + RBV in compensated cirrhosis or advanced fibrosis (SVR12 88% and 92%, respectively) have been presented here (ALLY-3+; Abs. LB-3)

Background

a Non-cirrhotic and compensated or decompensated cirrhotic, treatment-naive and-experienced, HIV/HCV coinfected, post-liver transplant.1. European Association for Study of Liver. J Hepatol 2015;63:199–236. 2. AASLD/IDSA/IAS-USA guidelines. Available at www.hcvguidelines.org. 3. Nelson DR, et al. Hepatology 2015;61:1127–1135. 2

http://www.hcvguidelines.org/

■ The French ATU (Temporary Authorisation for Use) program for DCV provided early, pre-market-authorization access to DCV for HCV patients with advanced liver disease and no other HCV treatment options

■ We report interim ATU findings on DCV + SOF ± RBV in GT 3-infected patients with advanced liver disease

Objective

3

■ Adult patients with:– METAVIR fibrosis F3 or abovea

or– Irrespective of fibrosis score: severe extrahepatic manifestations;

post-liver transplant HCV recurrence, or indication for liver or kidney transplant

■ Recommended regimen and treatment duration‒ DCV 60 mg QD + SOF 400 mg QD for 24 weeks‒ RBV use and/or shorter treatment duration (12 weeks) at physician’s discretion

■ Endpoints

‒ Efficacy: SVR12b at post-treatment Week 12 (PT12)‒ Safety: based on serious adverse events (SAEs), AEs, and

treatment discontinuation

Patients and Endpoints

a Biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);b HCV RNA < lower limit of quantification (LLOQ), target detected (TD), or target not detected (TND). 4

■ The safety population comprised patients with detectable HCV RNA at baseline who had 1 subsequent visit form completed

■ The primary efficacy population comprised patients within the safety population who had available HCV RNA data at PT12a

■ Treatment failure was defined as – HCV RNA LLOQ at PT12 (including

imputation)a

– Death before PT12– AE-related discontinuation without

achieving SVR12

Populations

a Missing PT12 data were back-imputed from PT24 if available. Where PT24 was missing, missing SVR12 visit data was imputed as a failure ( LLOQ at PT12) if HCV RNA was LLOQ at PT4. Where both PT4 and PT24 were missing, SVR12 failure was imputed if HCV RNA was LLOQ at end-of-treatment; b Total ATU population: 3886.

All GT 3 Patients in ATUb

N = 561

Safety PopulationN = 468

Primary Efficacy Population

N = 284

Excluded, 93• BL HCV RNA undetectable, 32• BL HCV RNA missing, 1• No visit form, 60

Excluded, 184• Follow-up < 12 weeks, 184

5

20.6%(n = 58)

DCV + SOF12 Weeks

1.8%(n = 5)

DCV + SOF + RBV12 Weeks

DCV + SOF24 Weeks

Treatment Regimens and Proportions

6a Excludes 2 patients with unknown treatment duration. Total efficacy population: 284.

58.9%(n = 166)

18.8%(n = 53)

DCV + SOF + RBV24 Weeks

Total: N = 282a

Baseline Characteristics

7

a DCV + SOF + RBV, n = 5; b Overall totals include data for 2 patients with missing regimen details (not shown);c Advanced fibrosis defined by biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);d Cirrhosis defined by biopsy, FibroScan ( 14.6 kPa), or FibroTest ( 0.75).All percentages are of patients with available data in indicated category. Missing data due to unknown: sex (n = 5); HCV RNA (n = 1); previous HCV treatment status (n = 2); cirrhosis status (n = 2); Child–Pugh category (n = 26); fibrosis stage (n = 2); platelet count (n = 20); albumin count (n = 26). 7

ParameterDCV + SOF ± RBVa

12 weeksn = 63

DCV + SOF24 weeksn = 166

DCV + SOF + RBV24 weeks

n = 53Overall

(N = 284)b

Age, median (range) years 53.4 (39–78) 55.0 (27–79) 53.2 (40–72) 54.1 (27–79)

Male, n (%) 43 (68.3) 123 (75.0) 40 (80.0) 208 (74.6)

HCV RNA, median (range) log10 IU/mL 5.99 (2.40–7.83) 6.00 (3.03–7.40) 5.60 (1.60–7.25) 5.94 (1.60–7.83)

Advanced fibrosis (F3),c n (%) 19 (30.2) 21 (12.7) 2 (3.8) 42 (14.8)

Cirrhosis,d n (%) 37 (58.7) 135 (82.3) 48 (90.6) 222 (78.7)

Child–Pugh A / B / C, n (%) 30 (83.3) / 3 (8.3) / 3 (8.3)

98 (85.2) / 15 (13.0) / 2 (1.7)

33 (76.7) / 9 (20.9) / 1 (2.3)

162 (82.7) /28 (14.3) / 6 (3.1)

Platelets < 100 ×109 cells/L, n (%) 18 (32.1) 55 (35.0) 27 (55.1) 102 (38.6)

Albumin ˂ 35 g/L, n(%) 19 (31.7) 39 (26.5) 14 (28.6) 74 (28.7)

Liver transplant recipient, n (%) 3 (4.8) 16 (9.6) 5 (9.4) 24 (8.5)

Pre-liver or renal transplant stage, n (%) 4 (6.3) 16 (9.6) 5 (9.4) 25 (8.8)

Treatment-experienced, n (%) 38 (60.3) 125 (76.2) 40 (75.5) 205 (72.7)

Coinfection with HIV / HBV, n (%) 7 (11.3) / 0 31 (18.7) / 5 (3.0) 3 (5.7) / 2 (3.7) 41 (14.4) / 7 (2.5)


8



12 weeksn = 63



n = 53Overall

(N = 284)b


Male, n (%) 43 (68.3) 123 (75.0) 40 (80.0) 208 (74.6)



Cirrhosis,d n (%) 37 (58.7) 135 (82.3) 48 (90.6) 222 (78.7)

Child–Pugh A / B / C, n (%) 30 (83.3) / 3 (8.3) / 3 (8.3)

98 (85.2) / 15 (13.0) / 2 (1.7)

33 (76.7) / 9 (20.9) / 1 (2.3)

162 (82.7) /28 (14.3) / 6 (3.1)


Albumin ˂ 35 g/L, n(%) 19 (31.7) 39 (26.5) 14 (28.6) 74 (28.7)






9



12 weeksn = 63



n = 53Overall

(N = 284)b


Male, n (%) 43 (68.3) 123 (75.0) 40 (80.0) 208 (74.6)



Cirrhosis,d n (%) 37 (58.7) 135 (82.3) 48 (90.6) 222 (78.7)

Child–Pugh A / B / C, n (%) 30 (83.3) / 3 (8.3) / 3 (8.3)

98 (85.2) / 15 (13.0) / 2 (1.7)

33 (76.7) / 9 (20.9) / 1 (2.3)

162 (82.7) /28 (14.3) / 6 (3.1)


Albumin ˂ 35 g/L, n(%) 19 (31.7) 39 (26.5) 14 (28.6) 74 (28.7)





Overall SVR12 in GT 3 by Regimen and Duration

12 Weeks 24 Weeks0

102030405060708090

100

10

4758

147166

55

4353

81.0

10088.6

81.1

Relapse: 6 Other VF: 2Death: 2DC due to AEs: 1

Relapse: 9Other VF: 7Death: 3

Relapse: 7Other VF: 3

HCV

RN

A <

LLO

QTD

/TN

D

DCV + SOF DCV + SOF + RBV

■ Overall SVR12 by regimen: 87% (194/224) for DCV + SOF; 83% (48/58) for DCV + SOF + RBV■ Overall SVR12 by treatment duration: 83% (52/63) for 12 weeks; 87% (190/219) for 24 weeks

DC, discontinuation; Other VF, undefined virologic failure. Data missing for 2 patients due to unknown treatment duration.

SVR12 in Patients Without Cirrhosis(70% With Advanced Fibrosis [F3])

11

12 Weeks 24 Weeks0

102030405060708090

100 96.0 100100

80.0

HCV

RN

A <

LLO

QTD

/TN

D (%

)


2425

45

2929

11

■ Overall SVR12 97% (58/60)– By regimen: 98% (53/54) for DCV + SOF; 83% (5/6) for DCV + SOF + RBV– By treatment duration: 96% (25/26) for 12 weeks; 97% (33/34) for 24 weeks

Data missing for 2 patients due to unknown treatment duration or cirrhosis status.

SVR12 in Patients With Cirrhosis

12

12 Weeks 24 Weeks0

102030405060708090

100

69.7

85.9

100

81.3

HCV

RN

A <

LLO

QTD

/TN

D (%

)

116135

2333

3948

44


■ Overall SVR12 82% (182/222)– By regimen: 83% (139/168) for DCV + SOF; 83% (43/52) for DCV + SOF + RBV– By treatment duration: 73% (27/37) for 12 weeks; 85% (155/183) for 24 weeks

Data missing for 2 patients due to unknown treatment duration or cirrhosis status.

SVR12 by Baseline Child–Pugh Score

13a 4 patients received RBV for 12 weeks, all were Child–Pugh A, and all achieved SVR12.Missing data for 26 patients of unknown Child–Pugh score, and 2 patients of unknown treatment duration.

0102030405060708090

100

80.090.0

84.8

33.3

70.6 70.0

HCV

RN

A <

LLO

QTD

/TN

D (%

)

Child–Pugh A Child–Pugh B or C

2430

26

90100

1217

2833

710

11

12 WeeksDCV + SOF ± RBVa

24 WeeksDCV + SOF

24 Weeks DCV + SOF + RBV

■ Overall SVR12:– Child–Pugh A: 87% (142/163)– Child–Pugh B: 67% (18/27)– Child–Pugh C: 50% (3/6)

Safety and Tolerability: Deaths and Serious AEs

14

a Respiratory distress/septic shock (n = 1), sepsis/pulmonary arterial hypertension (n = 1), septic shock (n = 1), liver decompensation (n = 1), acute kidney injury (n = 1) – all considered unrelated to treatment; multi-organ failure/hepatorenal failure of unreported causality (n = 1); unknown cause of death (n = 1); b Both received DCV + SOF + RBV. Treatment maintained for patient with hepatic encephalopathy. Treatment discontinued for patient with allergic dermatitis (achieved SVR12); c Blood/vascular disorders (n = 4); medical procedures (n = 5); general disorders (n = 3); neoplasm (n = 1); respiratory distress (n = 2); alcoholic hepatitis (n = 1); urinary retention (n = 1).

n (%) Total (N = 468)

Deathsa 7 (1.5)Serious AEs 44 (9.4)

SAEs reported as related to treatmentb

Hepatic decompensation (encephalopathy)Other (allergic dermatitis)

2 (0.4)1 (0.2)1 (0.2)

SAEs unrelated to treatmentHepatic decompensation (ascites, digestive bleeding, encephalopathy)Severe infection (dysentery, pneumonia, erysipelas)Hepatocellular carcinomaCholangiocarcinomaRenal impairmentLiver transplantOtherc

42 (9.0)8 (1.9)6 (1.3)7 (1.5)1 (0.2)2 (0.4)1 (0.2)

17 (3.8)

Safety and Tolerability: Common AEs and AE-Related Discontinuations

15a Allergic dermatitis (n = 1); neutropenia (n = 1); unspecified medical decision (n = 1).

n (%) Total (N = 468)

Discontinuations for AEsa 3 (0.6)Common AEs ( 3%)

AstheniaSleep disorder/InsomniaHeadacheDiarrheaFatigue

49 (10.5)30 (6.4)26 (5.6)18 (3.8)15 (3.2)

Summary and Conclusions

16

■ In this real-world setting, DCV + SOF ± RBV for 12 or 24 weeks was well tolerated and achieved high SVR12 in GT 3 patients with advanced liver disease– 97% in noncirrhotic patients, mostly with advanced fibrosis

– 87% in Child–Pugh A cirrhosis, and 82% in all cirrhosis

■ 24 weeks of DCV + SOF resulted in 86% SVR12 in cirrhotic patients– No impact of RBV use on SVR for 24 weeks of treatment (81% SVR12 with RBV)

– The role of RBV in DCV + SOF treatment < 24 weeks requires randomized evaluation in a larger dataset

■ These results show the pangenotypic, all-oral regimen of DCV + SOF ± RBV is an effective and well-tolerated option for patients with GT 3 infection and advanced liver disease

Acknowledgments

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■ The authors thank the patients and their families for their support and dedication, and all physicians, pharmacists, and medical staff at all hospital sites

■ Study management and analysis was performed by Lincoln

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

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