Expert Presentation Delivered by: Seng Gee Lim, MD Teerha ... · Expert Presentation Delivered by:...

1

Expert Presentation Delivered by: Seng Gee Lim, MD Singapore

Teerha Piratvisuth, MD Thailand

This enduring activity is supported by educational grants from AbbVie & Gilead Sciences, Inc.

This webcast is not sanctioned by the EASL conference organizers, nor is it an official part of the conference proceedings.

Endorsed by:

2

Abstract PS-098

Ledipasvir/Sofosbuvir for 12 Weeks Is Safe and Effective in Patients with Chronic Hepatitis C and Hepatitis B Coinfection: A Phase 3 Study in Taiwan

Chun-Jen Liu* 1, Wan-Long Chuang2, I-Shyan Sheen3, Horng-Yuan Wang4, Chi-Yi Chen5, Kuo-Chih Tseng6, Ting-Tsung Chang7, Benedetta Massetto8, Jenny Yang8, Gregory Camus8, Fangqiu Zhang8, Diana M. Brainard8, John G. McHutchison8, Tsung-Hui Hu9,

You-Chun Hsu10, Gin-Ho Lo11, Chi-Jen Chu12, Jyh-Jou Chen13, Cheng-Yuan Peng14, Ron-Nan Chien15, Pei-Jer Chen16

E-mail: [email protected]

1.  Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei

2.  Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung

3.  Chang Gung Memorial Hospital (CGMH), Taoyuan 4.  Mackay Memorial Hospital, Taipei 5.  Chia-Yi Christian Hospital

6.  Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi

7.  National Cheng Kung University Hospital, Tainan, Taiwan 8.  Gilead Sc., Foster City, United States 9.  Chang Gung Memorial Hospital (CGMH), Kaohsiung 10. Changhua Christian Hospital, Changhua 11. E-DA Hospital, Kaohsiung 12. Taipei Veterans General Hospital, Taipei 13. Chi Mei Hospital, Tainan 14. China Medical University Hospital, Taichung 15. Chang Gung Memorial Hospital, Keelung 16. National Taiwan University College of Medicine and Hospital,

Taipei, Taiwan

3

Background and Aims

•  Patients coinfected with HCV/HBV have more rapid liver disease progression and worse outcomes than patients monoinfected with either HBV or HCV.

•  Taiwan has among the highest prevalence of chronic HCV/HBV coinfection in Southeast Asia.

•  In Taiwan the standard of care for HCV/HBV coinfection is PEG/RBV for 24 or 48 weeks.

•  This study evaluated the safety and efficacy of an all-oral treatment with ledipasvir (LDV)/sofosbuvir (SOF) for 12 weeks in patients with chronic HCV and HBV coinfection.

Liu Chun-Jen, et al. Abstract #PS-098, EASL 2017.

4

Methods

•  Patients with or without compensated cirrhosis chronically infected with HCV GT1 or GT2 and HBV (positive for serum HBsAg) not currently receiving HBV treatment were enrolled into this open-label, ongoing study to receive LDV 90 mg/SOF 400 mg (once daily) for 12 weeks.

•  HBV DNA was monitored at all study visits during treatment.

•  The start of HBV treatment was based on the APASL guidelines.


5

Results •  A total of 111 patients (68 [61%] with GT1 and 43 [39%] with GT2) were enrolled

and treated. The majority were female (62%), treatment naive (67%), and non-cirrhotic (85%), with a mean age of 55 years (range 32-76) and mean BMI of 24.5 kg/m2 (range 17.3-33.8). All but one were HBeAg negative.

•  SVR12= 100%

•  HBV reactivation: 63%

•  ALT elevations: 5%

•  2% started HBV therapy

•  No patients discontinued treatment due to adverse events (AEs).

•  Three patients had serious AEs, one each of optic neuritis, post procedural bleeding and duodenal ulcer bleeding; none was considered drug related. The most common AEs reported (≥5% of patients) were headache, upper respiratory infection, and fatigue.


6

GS-007

ENDURANCE-3: Safety and Efficacy of Glecaprevir/Pibrentasvir Compared to Sofosbuvir

Plus Daclatasvir in Treatment-Naïve HCV Genotype 3-Infected Patients Without Cirrhosis

Graham R Foster1, Edward Gane2, Armen Asatryan3, Tarik Asselah4, Peter J Ruane5, Stanislas Pol6, Fred Poordad7, Catherine A Stedman8, Gregory Dore9, Stuart K Roberts10, Kelly Kaita11, John Vierling12, Hugo E Vargas13, Jens Kort3,

Chih-Wei Lin3, Ran Liu3, Teresa I Ng3, Federico J Mensa3

1.  Queen Mary University of London, Barts Health, London, United Kingdom

2.  Liver Unit, Auckland City Hospital, Auckland, New Zealand 3.  Abbvie Inc., North Chicago, IL, USA 4.  Centre de Recherche sur l’Inflammation, Inserm UMR 1149,

Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France 5.  Ruane Medical & Liver Health Institute, Los Angeles, California,

United States 6.  Group Hospitalier Cochin-Saint Vincent De Paul, Paris, France 7.  The Texas Liver Institute, San Antonio, Texas, United States

8.  Christchurch Hospital and University of Otago, Christchurch, New Zealand

9.  Kirby Institute, UNSW Australia and St. Vincent’s Hospital, Sydney, Australia

10. Alfred Hospital, Melbourne Australia 11.  University of Manitoba, Winnipeg, Manitoba, Canada 12. Baylor College of Medicine, Houston, Texas, United States 13. Mayo Clinic, Phoenix, Arizona, United States

7

HCV Genotype 3 and Treatment Options •  Chronic hepatitis C Virus (HCV) genotype (GT) 3 infection is common

and progressive

–  Prevalent among people who inject drugs

•  In GT3, DAA therapies have shown lower rates of SVR

•  EASL-recommended treatments for treatment-naïve patients without cirrhosis are:

–  Sofosbuvir + daclatasvir (12 – 24 weeks)

–  Sofosbuvir/velpatasvir (12 weeks)

•  Shorter treatment duration could enhance patient adherence and access to treatment

Foster Graham R, et al. Abstract #GS-007, EASL 2017.

8

ENDURANCE-3: Objective and Study Design

Arm C: 8-week treatment duration Per discussion with regulatory authorities after phase 2 treatment data became available, an 8 week treatment Arm of G/P was added to the study design

•  SVR12: Non-inferiority of 8 weeks of G/P compared to 12 weeks of G/P*

SVR12

SVR12

SVR12

Weeks 0 12 24

G/P

20

Treatment Period

SOF + DCV

G/P N = 157 Arm C

8

Post-treatment Period

N = 233 Arm A

N = 115 Arm B

2:1

rand

omiz

ed

(2) n

on-in

ferio

rity

(1) n

on-in

ferio

rity

*Endpoint was tested only after 12 weeks of G/P was determined non-inferior to 12 weeks of SOF + DCV Foster Graham R, et al. Abstract #GS-007, EASL 2017.

9

Baseline Demographics and Clinical Characteristics

Characteristic G/P

12 weeks N = 233

SOF + DCV 12 weeks N = 115

G/P 8 weeks N = 157

Male, n (%) 121 (52) 52 (45) 92 (59)

White race, n (%) 205 (88) 103 (90) 134 (85)

Age, median years (range) 48 (22 – 71) 49 (20 – 70) 47 (20 – 76)

BMI, median kg/m2 (range) 25 (17 – 49) 25 (18 – 42) 26 (18 – 44)

HCV RNA, median log10 IU/mL (range) 6.1 (3.5 – 7.5) 6.0 (3.8 – 7.4) 6.1 (1.2 – 7.6)

History of Injection drug use, n (%) 149 (64) 73 (63) 104 (66) Baseline fibrosis stage, n (%)

F0 – F1 201 (86) 97 (84) 122 (78)

F2 12 (5) 8 (7) 8 (5)

F3 20 (9) 10 (9) 27 (17)

Subtype GT3a, n/N (%) 226/229 (99) 113/113 (100) 154/155 (99)

2:1 randomized non-randomized

BMI, body mass index; DCV, daclatasvir; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir HCV subtype determined by phylogenetic analysis; N = total number of patients with sequence data available Foster Graham R, et al. Abstract #GS-007, EASL 2017.

10

ENDURANCE 3: SVR12

(1) -1.2% (95% CI -5.6 – 3.1)

(2) -0.4% (97.5% CI -5.4 – 4.6)

(1) non-inferior

Non-inferiority: Lower bound of the confidence interval (CI) of the difference in SVR12 must be above -6%*

Both G/P treatments met non-inferiority criteria for the primary endpoint

(2) non-inferior

95 97 95

0

20

40

60

80

100

G/P SOF + DCV G/P

SVR

12 (%

Pat

ient

s)

Treatment

222 233

111 115

149 157

12 weeks Duration 12 weeks 8 weeks Foster Graham R, et al. Abstract #GS-007, EASL 2017.

11

Abstract GS-006

EXPEDITION-I: Efficacy and Safety of Glecaprevir/Pibrentasvir in Adults with Chronic

Hepatitis C Virus Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Cirrhosis

Xavier Forns* 1, Sam Lee2, Joaquin Valdes3, Sabela Lens1, Reem Ghalib4, Humberto Aguilar5, Franco Felizarta6, Tarek Hassanein7, Holger Hinrichsen8, Diego Rincon9, Rosa Morillas10, Stefan Zeuzem11, Yves Horsmans12, David Nelson13, Yao Yu3, Tami Pilot-Matias3,

Chih-Wei Lin3, Federico Mensa3

1.  Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain 2.  University of Calgary, Calgary, Canada 3.  ABBVIE, North Chicago 4.  Texas Digestive Disease Consultants, Arllington 5.  Louisiana Research Center, LLC, Shreveport 6.  Private Practice, Bakersfield 7.  Southern California Liver Centers and Southern California Research

Center, Coronado, United States 8.  Gastroenterology-Hepatology Center Kiel, Kiel, Germany 9.  Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 10.  Liver Section and CIBERehd, Department of Gastroenterology, Hospital

Universitari Germans Trias i Pujol, Badalona, Spain

11.  J.W. Goethe University, Frankfurt, Germany 12.  Cliniques Universitaires Saint-Luc, Université Catholique de Louvain,

Brussels, Belgium 13.  Division of Gastroenterology, Hepatology and Nutrition, Department of

Medicine, College of Medicine, University of Florida, Gainesville, United States

12

Next Generation Direct-Acting Antivirals

In vitro:1

•  High barrier to resistance •  Potent against common NS3 polymorphisms (eg, positions 80, 155, and

168) and NS5A polymorphisms (eg, positions 28, 30, 31 and 93) •  Synergistic antiviral activity

Clinical PK & metabolism:

•  Once-daily oral dosing •  Minimal metabolism and primary biliary excretion •  Negligible renal excretion (<1%)

Glecaprevir (formerly ABT-493)

pangenotypic NS3/4A protease inhibitor

Pibrentasvir (formerly ABT-530)

pangenotypic NS5A inhibitor

Coformulated: G/P

GLE PIB

G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg; Glecaprevir was identified by AbbVie and Enanta Ng TI, et al. Antimicrobial Agents and Chemotherapy, 2017. Forns Xavier, et al. Abstract #GS-006, EASL 2017.

13

EXPEDITION-1: Objective and Study Design

Objective Evaluate the efficacy and safety of G/P for 12 weeks in patients with HCV GT1, 2, 4, 5 or 6 infection and compensated cirrhosis * Open-Label Treatment G/P is coformulated and dosed once daily as three 100 mg/40 mg plus for a total dose of 300 mg/120 mg.

G/P 300 mg/120 mg N=146

0 Week 12 Week 24 Week 36

SVR12 assessment Patients were enrolled at 40 study sites in Belgium, Canada, Germany, South Africa, Spain, and the United States

* GT3 patients with compensated cirrhosis enrolled in a separate study (SURVEYOR-II, part 3; n=40, 98% SVR12) Forns Xavier, et al. Abstract #GS-006, EASL 2017.

14

Characteristic 12-Week G/P N = 146

Male, n (%) 90 (62) Age, median (range), years 60 (26-88) White race,* n (%) 120 (82) BMI, median (range), kg/m2 29 (18-55) HCV genotype, n (%)†

1a 48 (33) 1b 39 (27) 2 34 (23) 4 16 (11) 5 2 (1) 6 7 (5)


G/P, glecaprevir/pibrentasvir; BMI, body mass index * Race and ethnicity are self-reported †Genotype determined by the Versant HCV Genotype Inno-LiPA Assay Version 2.0. Forns Xavier, et al. Abstract #GS-006, EASL 2017.

15


12-Week G/P N = 146

HCV RNA, median (range) log10 IU/mL 6.1 (3.1–7.4) Treatment-naïve 110 (75) Treatment-experienced 36 (25) IFN-based (IFN/pegIFN ± RBV) 25 (69) SOF-based (SOF + RBV ± pegIFN) 11 (31) Platelet count <100,000, 109/L 29 (20) INR <1.7 144 (99) Total bilirubin ≥2, mg/dL 5 (3) Albumin ≥ LLN 145 (99) Child-Pugh score at screening 5 133 (91) 6 13 (9)

IFN, interferon; SOF, sofosbuvir; INR, international normalized ratio; LLN, lower limit of normal (33) Forns Xavier, et al. Abstract #GS-006, EASL 2017.

16

SVR12 by Intent-to-Treat (ITT) Analysis

99 100 100 100 100 99

0

20

40

60

80

100

GT1 GT2 GT4 GT5 GT6 Total

% P

atie

nts

with

SVR

12

•  No treatment-emergent substitutions were present in NS3

•  In NS5A, Y93N was present at baseline; Y93N, Q30R and H58D were present at the time of failure

89 90

31 31

16 16

2 2

7 7

145 146

*Patient with HCV GT1a infection relapsed at PTW8 Forns Xavier, et al. Abstract #GS-006, EASL 2017.

17

Abstract PS-102

Utilization of Sofosbuvir/Velpatasvir in Genotype 2-6 HCV: Real-World Experience from the

TRIO Network Michael Curry* 1, Bruce Bacon2, Douglas Dieterich3, Steven Flamm4, Kris Kowdley5, Scott Milligan6, Naoky Tsai7, Zobair Younossi8,

Nezam Afdhal1

1.  Beth Israel Deaconess Medical Center, Boston 2.  Saint Louis University School of Medicine, Saint Louis 3.  Icahn School of Medicine at Mount Sinai, New York 4.  Northwestern University Feinberg School of Medicine, Chicago 5.  Liver Care Network, Swedish Medical Center, Seattle 6.  Trio Health Analytics, LaJolla 7.  Queens Medical Center, University of Hawaii, Honolulu 8.  Department of Medicine, Center for Liver Diseases, Inova Fairfax, Falls Church, United States

18

Study Data

Inclusion criteria:

•  18 year or older patients

•  Not enrolled in a clinical trial

•  Initiated anti-HCV therapy in 2016

•  GT2-6 HCV

Data collection as of Mar 1 2017

Representation from 40 US states and DC

Majority of care in community practice

Metric Academic Community Total

Patients 338 1489 1827

Physicians 111 652 763

Curry Michael, et al. Abstract #PS-102, EASL 2017.

19

Per Protocol SVR12 SOF + RBV and SOF-VE +/- RBV for Genotype 2 HCV

94% 88%

95% 94% 96% 97% 95% 97% 95% 97%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

All TE TN F4 F0-3

SOF+RBV SOF-VEL+/-RBV

238 252

91 94

30 34

21 22

208 218

70 72

48 51

21 22

188 196

70 72


20

Per Protocol SVR12 DCV + SOF +/- RBV and SOF-VEL +/- RBV for Genotype 3 HCV

96% 93% 97% 93% 98% 97%

92% 98%

93% 100%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

All TE TN F4 F0-3

SOF+RBV SOF-VEL+/-RBV

266 276

66 68

52 56

11 12

214 220

55 56

67 72

14 15

196 201

52 52


21

Patient Disposition LDV-SOF +/- RBV and SOF-VEL +/- RBV for Genotype 4-6 HCV

SVR (PP): 94% (127/135) SVR (PP): 91% (10/11)

LDV-SOF +/- RBV n=204 (113 GT4, 1 GT5, 90 GT6)

In therapy n=2

Discontinued n=1

LTFU n=11

Death n=2

Completed Therapy n=188

SVR Pending n=53

SVR Not Achieved n=8

SVR Achieved n=127

SOF-VEL +/ RBV n=38 (13 GT4, 25 GT6)

In therapy n=1

Discontinued n=2

LTFU n=0

Death n=0

Completed Therapy n=35

SVR Pending n=24

SVR Not Achieved n=1

SVR Achieved n=10


22

Abstract PS-097

Sustained Virological Response for 94% of People Treated with Low-Cost, Legally Imported Generic Direct Acting Antivirals for Hepatitis C: Analysis of

1087 Patients in 4 Treatment Programmes James Freeman* 1, Giten Khwairakpam2, Julia Dragunova3, Sergey Golovin3, James Wang4, Andrew Hill5, Vicky Houghton-Price6,

Rachel Smith6, Roxanna Korologou-Linden7, Greg Jefferys8

1.  GP2U Telehealth FixHepC, Hobart, Australia 2.  TREAT Asia/amfAR, Bangkok, Thailand 3.  International Treatment Preparedness Coalition Russia, St Petersburg, Russia 4.  Ci Run Health Information Consulting Co. Ltd, Kunming, China 5.  St Stephens AIDS Trust 6.  METAVIROLOGY LTD 7.  Faculty of Medicine, Imperial College London, London, United Kingdom 8.  University of Tasmania, Hobart, Australia

23

Background and Aims

•  High prices of branded DAAs prevent universal access to treatment in most countries. However, 12-weeks of generic sofosbuvir/daclatasvir (SOF/DCV) can be purchased for US$450 in India or Bangladesh.

•  Several generic DAAs have been approved by international donor agencies, meeting quality control standards.

Freeman James, et al. Abstract #PS-097, EASL 2017.

24

Methods •  Generic versions of sofosbuvir (SOF), ledipasvir (LDV), daclatasvir

(DCV) and velpatasvir were sourced from generic suppliers in India, Bangladesh, Egypt and China.

•  Four treatment access programmes in Russia, South East Asia and Australia were included in the analysis.

•  The choice of DAAs and treatment length were determined from baseline HCV genotype and stage of fibrosis.

•  This analysis includes available data from 1087 patients being monitored in hospitals, private doctors and clinics in 42 countries worldwide.


25

Results •  1087 patients were treated; 524 received SOF/DCV, 462 SOF/LDV, 99 received

SOF/RBV, 1 received SOF/VEL and 1 received SOF/LDV/DCV. The median length of treatment was 12 weeks.

•  Overall, the patients were 60% male with a mean age of 43.7 years; 56% were Genotype 1 and the mean baseline HCV RNA was 6.9 log IU/mL.


SOF/RBV SOF/LDV (+/- RBV) SOF/DCV (+/- RBV)

RVR 52/58 (90%) 208/252 (83%) 253/300 (84%)

EOT 42/42 (98%) 293/299 (98%) 298/302 (99%)

SVR4 31/31 (100%) 235/249 (94%) 224/241 (99%)

SVR12 21/23 (91%) 194/212 (92%) 184/213 (86%)

26

PS-035

Among Cirrhotic Patients with a Hepatitis C Sustained Viral Response, the Risk of De-Novo Hepatocellular Carcinoma Relates to Baseline

Factors and Not the Use of Direct Acting Antivirals: Results from a Nationwide Cohort

Hamish Innes* 1, Stephen T. Barclay2, Peter C. Hayes3, Andrew Fraser4, John F. Dillon5, Adrian Stanley2, Andy Bathgate3, Scott McDonald1, David Goldberg6, Heather Valerio1, Ray Fox7, Nick Kennedy8, Pete Bramley9, Sharon J. Hutchinson1

Email: [email protected]

1.  School of Health and Life Sciences, Glasgow Caledonian University 2.  Glasgow Royal Infirmary, Glasgow 3.  Royal Infirmary Edinburgh, Edinburgh 4.  Aberdeen Royal Infirmary, Aberdeen 5.  Ninewells Hospital and Medical School, Dundee 6.  Health Protection Scotland 7.  The Brownlee Centre, Glasgow 8.  Monklands Hospital, Lanarkshire 9.  Stirling Royal Infirmary, Stirling, United Kingdom

27

Background

Author Journal, Year

Recurrence or

Occurrence? Country, Setting Sample

Frequency of HCC

Occurrence/Recurrence

Control Group

Reig, et al J Hepatol, 2016 Recurrence

4 referral hospitals,

Spain

Treated with IFN-free regimen after

successfully treated HCC,

N=59

28% after median

follow-up of 5.7 months

None

Conti, et al J Hepatol, 2016 Recurrence

Liver clinics in Bologna,

Italy

Treated with IFN-free regimen after

successfully treated HCC,

N=58

29% by 24 weeks post-treatment follow-up

None

Conti, et al J Hepatol, 2016 Occurrence

Liver clinics in Bologna,

Italy

Cirrhotic patients treated with IFN-

free therapy, N=285

3.2% HCC occurrence

by 24 weeks post

treatment follow-up

None

Cardoso, et al

J Hepatol, 2016 Occurrence One clinic in

Portugal

Cirrhotic patients achieving SVR via IFN-free therapy,

N=54

7.4% after median 12

months follow-up

None

Innes Hamish, et al. Abstract #PS-035, EASL 2017.

28

Methods: Study Fundamentals

•  Retrospective cohort study using –  Scottish HCV clinical database (downloads @ April 2016)

–  Subsequent medical chart review (carried out February–March 2017)

•  Definition of study cohort –  Inclusion criteria

•  SVR attainment in 1997–2016

•  Liver cirrhosis at time of starting treatment

–  Exclusion criteria •  Diagnosis of HCC prior to treatment

•  HBV/HIV co-infection

•  Attendance at a clinic with incomplete database or otherwise not able to participate in medical chart review


29

Methods: Study Fundamentals •  Primary outcome event: first time diagnosis of HCC by cross-sectional

imaging or biopsy

•  Wide range of baseline patient characteristics extracted:

–  Age; gender ethnicity; postcode deprivation score; Child Pugh score; thrombocytopenia; alphafetoprotein; diabetes; alcohol history; smoking history; drug use history; prior genotype; clinic attended; number of prior treatment failures

•  Survival analysis approach adopted

–  Start time=commencement of treatment

–  Stop time=earliest of: HCC occurrence; death; or reaching 31 Jan 2017.

–  Used Cox regression to assess univariate and multivariate association between regimen (IFN-free Vs. IFN-containing) and HCC.


30

Results: Baseline Description of the Cohort (N=857)

Characteristic % of Cohort (N=857)

Demographics Average age Mean: 49 years (sd: 8) White ethnicity 92% Male gender 75%

Health Behaviours

History of heavy alcohol use 44% Current tobacco smoker 73% History of intravenous drug use 70%

Clinical

Thrombocytopenia (<100/ 109 /L) 28%

Child Pugh B/C 15% Diabetes 9%

Treatment Treatment experienced 35%

IFN-free regimen 32%


31

Key Differences in Characteristics IFN-Containing Patients and IFN-Free Patients

Characteristic

Regimen

P-Value IFN-containing

(N=585)

IFN-free (N=272)

Mean age 48.1 years 52.1 years <0.001

Thrombocytopenic (<100 per 109/L) 22% 39% <0.001

Child Pugh B or C 9% 30% <0.001

Number of prior failed treatment episodes

0 73% 48% <0.001 1 21% 35%

≥2 7% 17% Innes Hamish, et al. Abstract #PS-035, EASL 2017.

32

Follow-up Time and Outcome Events, by Treatment Regimen

Regimen IFN-

containing (N-585)

IFN-free (N=272)

Follow-up, person years

Total 2697 475

Median per patient (IQR) 3.5 (2.2-5.6) 1.7 (1.4-2.0)

Outcome events (i.e. HCC occurrence)

Total # 34 12 # occurring <24 weeks post-treatment 6 5

# occurring ≥24 weeks post-treatment 28 7

Median time to event (min-max range)

2.5 yrs (0.3-8.5)

0.9 yrs (0.5-2.0)

Crude rate, per 100 persons years 1.26 2.52


33

Patient Characteristics Associated with HCC Occurrence in Univariate Analysis


34

Association Between IFN-Free Versus IFN-Containing Therapy and HCC Occurrence, in Univariate and Multivariate Analysis

* Multivariate analysis includes adjustment for: age, gender, ethnicity, Child Pugh score, thrombocytopenia, alphafetoprotein, genotype, treatmentexperience and clinic location Innes Hamish, et al. Abstract #PS-035, EASL 2017.

35

Conclusions

1.  There is no evidence that IFN-free therapy increases the risk of HCC occurrence in patients achieving an SVR

2.  Baseline characteristics of patients treated with IFN-free regimens differ from those treated with IFN- containing regimens

3.  Multivariate analysis demonstrated that the risk of HCC occurrence was equivalent between these two groups of patients


36

PS-034

Identifying Residual Risk of Hepatocellular Carcinoma Following Hepatitis C Virus Eradication in Compensated Cirrhosis: Decision-Tree and Random Forest Models Developed in the French Multicenter

Prospective ANRS CO12 CirVir Cohort

Etienne Audureau* 1, Valérie Bourcier2, Richard Layese1, Carole Cagnot3, Patrick Marcellin4, Dominique Guyader5, Stanislas Pol6, Dominique Larrey7, Françoise Roudot-Thoraval8, Pierre Nahon2 and ANRS CO12 CirVir group

1.  Public Health, CHU Henri Mondor, Créteil 2.  Hepatology, CHU Bondy, Bondy 3.  ANRS, Paris 4.  Hepatology, CHU Beaujon, Clichy 5.  Hepatology, CHU Rennes, Rennes 6.  Hepatology, CHU Cochin, Paris 7.  Hepatology, CHU Montpellier, Montpellier 8.  CHU Henri Mondor, Créteil, France

37

Methods •  Data were collected from 1253 patients with compensated biopsy-

proven HCV-cirrhosis recruited in 35 centres and prospectively followed-up.

•  During a median follow-up of 54.2 months, 179 (14.3%) patients developed HCC and 637 (50.8%) achieved SVR.

•  SVR is most important variable for predicting HCC.

•  5 additional variables independently associated with occurrence of HCC:

–  Age>50 years

–  Past excessive alcohol intake

–  Low platelet count

–  Increased AFP and GGT serum levels

Audureau Etienne, et al. Abstract #PS-034, EASL 2017.

38

Figure. Decision Tree from CART Survival Analysis

AFP: Alpha-fetoprotein; GGT: Gamma-Glutamyl Transpeptidase GGT; PT: Prothrombin Time; SVR: Sustained Virological Response Audureau Etienne, et al. Abstract #PS-034, EASL 2017.

39

Conclusions •  Risk factors for hepatocarcinogenesis differ according to SVR status.

•  In patients with compensated cirrhosis, HCV eradication should be achieved before the onset of liver function impairment and HCC surveillance be implemented after 50 years in all cases following SVR.

Audureau Etienne, et al. Abstract #PS-034, EASL 2017.

40

Abstract PS-154

Multiclass Hepatitis C Virus Resistance to Direct Acting Antivirals in Real Life Interferon-Free

Regimens Failures Advocates for Tailored Second-Line Therapies

Velia Chiara Di Maio* 1, Valeria Cento1, Ilaria Lenci2, Marianna Aragri1, Silvia Barbaliscia1, Simona Francioso2, Stefania Paolucci3, Michela Melis4, Gabriella Verucchi5, Nicola Coppola6, Carlo Federico Magni7, Valeria Micheli8, Teresa Pollicino9, Tina Ruggiero10, Francesco Santopaolo2, Simona Landonio7, Alessandro Mancon8,

Mario Starace6, Ada Bertoli1, Francesco Paolo Antonucci1, Cecilia D'Ambrosio11, Vincenza Calvaruso12, Filomena Morisco13, Caterina Pasquazzi14, Ivana Maida4, Antonio Picciotto15, Antonio Di Biagio 16, Bianca Bruzzone17, Laura Sticchi17, Valeria Ghisetti10, Raffaele Cozzolongo18, Dante Romagnoli19, Vincenzo Boccaccio20, Antonio Grieco21, Jacopo Vecchiet22, Gabriella D’Ettorre23, Manuela Merli24, Giovanni Battista Gaeta25, Alessia Ciancio26, Letizia Marinaro 10, Pietro Andreone27,

Giorgio Barbarini28, Roberto Gulminetti29, Valeria Pace Palitti30, Pierluigi Tarquini31, Massimo Puoti32, Vincenzo Sangiovanni33, Giorgio De Stefano33, Alessia Giorgini34, Maurizio Paoloni35, Nicola Caporaso13, Sergio Babudieri4, Guido Gubertini7, Savino Bruno20, Massimo Andreoni36, Adriano Pellicelli11, Giustino Parruti37,

Giovanni Raimondo9, Fausto Baldanti3, Antonio Craxì12, Mario Angelico2, Carlo Federico Perno1, Francesca Ceccherini-Silberstein1 and HCV Virology Italian Resistance Network Group (Vironet C)

1.  Department of Experimental Medicine and Surgery, University of Rome Tor Vergata 2.  Hepatology Unit, University Hospital of Rome Tor Vergata, Rome 3.  Virologia Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia 4.  Infectious Diseases Unit, University of Sassari, Sassari 5.  Policlinico S. Orsola-Malpighi, Bologna 6.  Infectious Diseases, Second University of Naples, Naples 7.  Division of Infectious Disease, Hospital Sacco of Milan 8.  Clinical Microbiology,Virology and Bioemergencies, ASST Fatebenefratelli Sacco, Milan 9.  Department of Internal Medicine, University Hospital of Messina, Messina 10.  Infectious Diseases, “Amedeo di Savoia” Hospital, Turin 11.  Hepatology Unit, San Camillo Forlanini Hospital, Rome 12.  Gastroenterology, “P. Giaccone” University Hospital, Palermo 13.  Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples 14.  Infectious Diseases, Sant’Andrea Hospital – “La Sapienza” University, Rome 15.  Division of Hepatology, IRCCS San Martino, IST Genova 16.  Infectious Disease, IRCCS AOU San Martino – IST 17.  Hygiene Unit, IRCCS AOU San Martino-IST, Genoa 18.  Department of Gastroenterology, Scientific Institute for Digestive Disease "Saverio de Bellis"

Hospital, Castellana Grotte, Bari 19.  Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio

Emilia, Modena 20.  Internal Medicine, Humanitas University, Rozzano, Milan 21.  Liver Transplant Unit, Catholic University of Rome, Rome 22.  Infectious Disease Clinic, Hospital of Chieti, Chieti 23.  Department of Public Health and Infectious Diseases 24.  Gastroenterology, Sapienza University of Rome, Rome 25.  Infectious Diseases and Viral Hepatitis Unit, Second University, Naples 26.  Unit of Gastroenterology, University of Turin, Turin 27.  Department of Medical and Surgical Sciences, University of Bologna, Bologna 28.  Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo 29.  Institute of Infectious Diseases, University of Pavia, Pavia 30.  Hepatology Unit, Pescara General Hospital, Pescara 31.  Infectious Disease, Hospital "G. Mazzini", Teramo 32.  Department of Infectious Diseases, Hospital Niguarda Ca’Granda, Milan 33.  Hospital Cotugno, Naples 34.  General Medicin Unit, SST Santi Paolo e Carlo, Milan 35.  Infectious Disease Unit, Avezzano General Hospital, Avezzano 36.  Infectious Diseases, University Hospital of Rome Tor Vergata, Rome 37.  Infectious Disease Unit, Pescara General Hospital, Pescara, Italy

41

Methods

•  Among 325 patients failing a DAA-IFN free regimen, 261 (GT1a-1b-2c-3a/h-4a/d/n/r=57-91-12-64-37; 79.4% cirrhotic; 70.6% treatment-experienced, 16 with DAA), with available resistance test at failure in NS3/NS5A/NS5B (by Sanger sequencing) were analyzed.

Di Maio Velia Chiara, et al. Abstract #PS-154, EASL 2017.

42

Results •  Interestingly, 4.2% of failures had a misclassified genotype: in particular, 7 previously

classified as GT1, were GT3a failing 3D ± RBV. •  Overall, 59.0% of patients showed at least one RAS related to the DAA-failure; RASs

prevalence was higher in breakthrough/non-responders than in relapsers (92.3% vs 50.9%, p <0.001)

•  RASs prevalence varied according to the DAA-class used (92.4% NS5A-RASs [N = 105], 72.3% NS3-RASs [N = 101], 34.5% DSV-RASs [N = 29)], 20.6% SOF-RASs [N = 218]) and according to HCV-GT. In NS5A-failing patients, Y93H was the most frequent major NS5A-RAS (61.9%), though with different prevalence among genotypes (15.4% GT1a; 90.0% GT1b; 82.6% GT3a; 40.0% GT4).

•  Furthermore, 40.0% of patients presented >2 NS5A-RASs, with complex patterns more frequently in GT1b failures (67.5%, e.g. Y93H+L31M/I).

•  Failures to SOF regimens showed frequent presence of L159F ± C316N (14.7%), particularly in GT1b (37.3%), followed by S282T in 3.6% (higher in GT4).

•  Notably, 42.9% of patients treated with >2 DAA classes showed multiclass-resistance, including 100% NS3-NS5A-failures, and 65.5% in 3D-failures.

•  Finally, 11 patients, all cirrhotic, experienced at least 2 subsequent virologic failures to IFN-free DAA regimens.


43

Conclusions

•  In this real life setting, RASs prevalence at failure was remarkably high in all genes tested (with a partial exception for NS5B).

•  This multiclass-resistance advocates for HCV resistance testing at failure in all 3 genes for the best second-line therapeutic tailoring.


44

Abstract PS-156

MAGELLAN-1, Part 2: GLE/PIB for 12 or 16 Weeks in Patients with CHC GT1 or 4 and Prior DAA

Treatment Failure Fred Poordad1, Stanislas Pol2, Armen Asatryan3, Maria Buti4, David Shaw5, Christophe Hézode6, Franco Felizarta7, Robert W

Reindollar8, Stuart C Gordon9, Stephen Pianko10, Michael W Fried11, David E Bernstein12, Joel Gallant13, Chih-Wei Lin3, Yang Lei3, Teresa I Ng3, Tami Pilot-Matias3, Jens Kort3, Federico Mensa3

1.  The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA

2.  Groupe Hospitalier Cochin-Saint Vincent De Paul, Paris, France 3.  AbbVie Inc., North Chicago, IL, USA 4.  Vall d’Hebron University Hospital, Barcelona, Spain 5.  Royal Adelaide Hospital, Adelaide, Australia 6.  Hôpital Henri Mondor, Université Paris-Est, Créteil, France 7.  Private Practice, Bakersfield, California, USA 8.  Piedmont Healthcare/Carolinas Center for Liver Disease,

Statesville, North Carolina, USA 9.  Henry Ford Health System, Detroit, Michigan, USA 10.  Caulfield Endoscopy, Caulfield South, Victoria, Australia

11.  University of North Carolina, Chapel Hill, North Carolina, United States

12.  North Shore University Hospital, Manhasset, New York, United States

13.  Southwest CARE Center, Santa Fe, New Mexico, United States

45


In vitro:1

•  High barrier to resistance •  Potent against common NS3 polymorphisms (eg, positions 80, 155, and

168) and NS5A polymorphisms (eg, positions 28, 30, 31 and 93) •  Synergistic antiviral activity







Coformulated: G/P

GLE PIB

G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg; Glecaprevir was identified by AbbVie and Enanta Ng TI, et al. Antimicrobial Agents and Chemotherapy, 2017; Poordad Fred, et al. Abstract #PS-156, EASL 2017.

46

Part 2 of MAGELLAN-1: Objective and Study Design

Objective •  Determine the efficacy and safety of G/P for 12 or 16 weeks in patients with

chronic HCV GT1 or GT4 infection and prior DAA failure, including those with compensated cirrhosis

G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg Weeks

SVR12

0 12 24

G/P

20

Treatment Period

N = 44 12 weeks

1:1

rand

omiz

ed

SVR12 G/P

16 28

N = 47 16 weeks

Poordad Fred, et al. Abstract #PS-156, EASL 2017.

47

Patient Criteria •  Key patient inclusion criteria

–  ≥18 years of age (no upper limit)

–  Chronic HCV GT1, 4, 5 or 6 infection (HCV RNA ≥1000 IU/mL)

–  History of virologic failure to at least one DAA-containing treatment •  NS3/4A protease inhibitors: PTV/r, SMV, ASV, TVR, or BOC

•  NS5A inhibitors: DCV, LDV, or OBV

–  Without cirrhosis or with compensated cirrhosis (Child-Pugh ≤6 at screening)

•  Key patient exclusion criteria –  Discontinuation of prior DAA treatment regimen for reasons other than virologic failure

–  HBV or HIV coinfection or infection with more than one HCV genotype

–  Alanine or aspartate aminotransferase >10 × ULN

–  Albumin <LLN or <2.8 g/dL for those with cirrhosis

–  Platelets < 90,000 or < 60,000 cells/mm3 for those with cirrhosis

–  Creatinine clearance < 50 mL/min


48


*Genotype and subtype determined by phylogenetic analysis for samples with available sequences †One patient had GT1, based on LiPA analysis, but was not subtyped BMI, body mass index; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus Poordad Fred, et al. Abstract #PS-156, EASL 2017.

Characteristic G/P

12 weeks N = 44

G/P 16 weeks

N = 47 Male, n (%) 31 (70) 33 (70) White race, n (%) 34 (77) 35 (75) Black race, n (%) 9 (20) 11 (23) Age, median years (range) 57 (22 – 67) 56 (36 – 70) BMI, median kg/m2 (range) 28 (21 – 41) 29 (20 – 52) HCV RNA, median log10 IU/mL (range) 6.1 (4.7 – 7.2) 6.3 (4.7 – 7.1) Compensated cirrhosis, n (%) 15 (34) 12 (26) HCV subtype*, n (%) 1a 35 (80) 32 (71) 1b 8 (18) 10 (22) 1e 0 1 (2) 4 1 (2) 3 (6) 1 (not subtyped) 0 1† (2)

49

Clinical Characteristics Continued

NS3 PIs included: PTV, SMV, ASV, TVR, or BOC; NS5A inhibitors included: DCV, LDV, or OBV *Sofosbuvir (NS5B inhibitor) could be included in any prior treatment regimen †Only 44 patients had sequencing data available in each arm; percentages are based on N = 44; substitutions detected by next generation sequencing using 15% detection threshold at positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A DAA, direct-acting antiviral; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus; NS, non-structural protein; PI, protease inhibitor Poordad Fred, et al. Abstract #PS-156, EASL 2017.

Characteristic, n (%) G/P

12 weeks N = 44

G/P 16 weeks

N = 47 Previous DAA regimen class* NS3/4A PI only (NS5A inhibitor-naïve) 14 (32) 13 (28) NS5A inhibitor only (PI-naïve) 16 (36) 18 (38) NS3/4A PI + NS5A inhibitor 14 (32) 16 (34) Prior DAA treatment response On-treatment failure 14 (32) 13 (28) Virologic relapse 30 (68) 34 (72) Presence of key baseline substitutions† None 13 (30) 13 (30) NS3 only 2 (5) 4 (9) NS5A only 24 (55) 23 (52) NS3 + NS5A 5 (11) 4 (9)

50

SVR12 by Intent-to-Treat (ITT) Analysis

89 91

0

20

40

60

80

100

12 Weeks 16 Weeks

SVR

12 (%

Pat

ient

s)

SVR12 rate by cirrhosis Cirrhosis: 85% (23/27) No Cirrhosis: 91% (58/64)

Duration

Breakthrough Relapse

1 4

4 0

39 44

43 47


51

SVR12 by DAA Class in Prior Therapy

100 88

79

100 94

81

0

20

40

60

80

100

PI Only NS5A Only PI + NS5A PI Only NS5A Only PI + NS5A

SVR

12 (%

Pat

ient

s)

Prior Inhibitor Failure

12 weeks Duration 16 weeks

14 14

14 16

11 14

13 13

17 18

13 16


52

SVR12 by Presence of NS3A or NS5A Substitutions

Y93H/N at baseline: 100% (13/13) SVR12 in patients with NS5A inhibitor experience (PI-naïve)

Key baseline NS3 and NS5A substitutions were only present in patients with prior failure to both PI and NS5A inhibitors

5/9 of these patients achieved SVR12

Key NS3 positions: 155, 156, 168 Key NS5A positions: 24, 28, 30, 31, 58, 92, 93 OTVF: on-treatment virologic failure Poordad Fred, et al. Abstract #PS-156, EASL 2017.

100 100 83 100 100 96

0

20

40

60

80

100

None NS3 Only

NS5A Only

None NS3 Only

NS5A Only

SVR

12 (%

Pat

ient

s)

Baseline Substitutions

G/P: 12 weeks Regimen G/P: 16 weeks

13 13

2 2

20 24

13 13

4 4

22 23

3 relapse 1 OTVF 1 OTVF

53

Summary: MAGELLAN-1, Part 2 •  Patients with prior failure to PI containing regimens

(NS5A inhibitor-naïve):

–  100% SVR12 with 12 or 16 weeks of G/P treatment

•  Patients with prior failure to both PI- and NS5A inhibitor-containing regimens had lower SVR12 rates

•  Patients with prior failure to NS5A inhibitors (i.e., LDV or DCV); NS3/4A PI-naïve:

–  94% SVR12 with 16 weeks of G/P treatment with no relapse

–  No impact of baseline NS5A substitutions on SVR12

•  G/P for 12 or 16 weeks was well tolerated; Grade 3 lab abnormalities were rare, with no discontinuations due to AEs, and no DAA-related serious AEs


54

Abstract PS-159

Safety and Efficacy of the Fixed-Dose Combination Regimen of Uprifosbuvir (MK-3682) / Grazoprevir / Ruzasvir in Cirrhotic or Non-Cirrhotic Patients with Chronic HCV GT1 Infection Who Previously Failed

a Direct-Acting Antiviral Regimen (C-SURGE) Heiner Wedemeyer1, David Wyles2, K. Rajender Reddy3, Anne Luetkemeyer4, Ira Jacobson5, John Vierling6, Stuart Gordon7,

Ronald Nahass8, Stefan Zeuzem9, Janice Wahl10, Eliav Barr10, Bach-Yen Nguyen10, Michael Robertson10, Hee-Koung Joeng10, Hong Liu10, Patricia Jumes10, Frank Dutko10, Elizabeth Martin10

1.  Hannover Medical School, Hannover, Germany 2.  Denver Health Medical Center, Denver, CO, US 3.  University of Pennsylvania, Philadelphia, PA, US 4.  University of California, San Francisco, CA, US 5.  Mount Sinai Beth Israel, New York, NY, US 6.  Baylor College of Medicine, Houston, TX, US 7.  Henry Ford Health System, Detroit, MI, US 8.  ID Care, Hillsborough, NJ, US 9.  Goethe University Hospital, Frankfurt, Germany 10. Merck & Co., Inc., Kenilworth, NJ, US

55

Grazoprevir + Ruzasvir + Uprifosbuvir •  Co-formulated as a fixed-dose combination tablet; administered as 2 tablets

once-daily for a total daily dose of 100 mg grazoprevir (GZR), 60 mg ruzasvir (RZR), and 450 mg of uprifosbuvir (UPR; MK-3682).

•  GZR + RZR + UPR has been shown to be effective, safe, and well tolerated for treatment-naïve and peg-interferon/ribavirin-treatment experienced HCV GT1, 2 and 3-infected patients with SVR rates >90%1,2.

Gane EJ, et al. EASL, abstract SAT-139, 2016; Gane EJ et al. AASLD, abstract LB-15, 2015; Tong, et al. J Med Chem. 2017;60:290; Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

•  HCV NS5A inhibitor3 •  30 mg per tablet

•  HCV NS5B nucleotide polymerase inhibitor

•  225 mg per tablet •  HCV NS3/4A protease inhibitor •  50 mg per tablet

Uprifosbuvir (UPR)

Ruzasvir (RZR)

Grazoprevir (GZR)

56

C-SURGE: Study Design

SVR12* 1° Endpoint

GZR + RZR + UPR + RBV† (16 weeks), n=45

TW8 TW16 TW24 FW12

GZR + RZR + UPR (24 weeks), n=49

D1

GZR: 100 mg once-daily; RZR: 60 mg once-daily; UPR: 450 mg once-daily; TW= treatment week; FW=follow-up week; LDV=ledipasvir; SOF=sofosbuvir. *SVR12 = HCV RNA <15 IU/mL at 12 weeks after end of treatment (COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®). †RBV dose based on body weight (<65 kg=800 mg/d; 65-85 kg=1000 mg/d; >85-105 kg=1200 mg/d; >105 kg=1400 mg/d). Patients could be compensated cirrhotic (platelet cutoff=75,000/µL; excluded Child-Pugh B & C) or non-cirrhotic patients. Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

57

Demographics

16 Weeks + RBV, n=44*

24 Weeks without RBV, n=49

Overall GT1 N=93*

Male, n (%) 37 (84) 43 (88) 80 (86) Age, median years, (range) 61.0 (33 to 70) 60.0 (25 to 71) 60.0 (25 to 71) Race, White, n (%) 31 (71) 37 (76) 68 (73) HCV Genotype 1a, n (%) 40 (91) 40 (82) 80 (86) Non-cirrhotic, n (%) 25 (57) 27 (55) 52 (56) Cirrhotic, n (%) 19 (43) 21 (43)† 40 (43) NS5A RASs at baseline, n (%)‡ 32 (79) 46 (94) 78 (84) NS3 RASs at baseline, n (%)‡ 25 (57) 35 (71) 60 (65) Baseline HCV RNA >2,000,000 IU/mL, n (%) 29 (66) 33 (67) 62 (67) Median baseline HCV RNA (log10 IU/mL) 6.5 6.4 6.5 Previously failed: 12 - 24 weeks of LDV/SOF

26 (59)

31 (63) 57 (61)

8 weeks of LDV/SOF 9 (20) 5 (10) 14 (15) 12 weeks of EBR/GZR 9 (20) 13 (27) 22 (24)

*Does not include 1 patient in the 16 week + RBV arm who withdrew prior to beginning treatment. Cirrhosis = Liver biopsy at any time showing cirrhosis, Fibroscan result of >12.5kPa within 12 months of enrollment, or Fibrotest >0.75 and APRI >2 at time of enrollment. †One patient in 24 week arm had unknown cirrhosis status ‡NS5A RASs = any change from wild-type at 4 positions (28, 30, 31, or 93). NS3 RASs = any change from wild-type at 14 positions (36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175). RASs detected by next generation sequencing performed with a 15% sensitivity threshold. Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

58

SVR12 (Full Analysis Set; Modified Full Analysis Set*)

98 100 100 100

0

20

40

60

80

100

Full Analysis Set Modified Full Analysis Set

SVR

12 (%

with

HC

V R

NA

<15

IU/m

L; 9

5% C

I)

16 weeks + RBV 24 weeks (no RBV)

SVR12 = % of patients with HCV RNA <15 IU/mL at 12 weeks after end of treatment. Full analysis set = all patients who received at least one dose of study medication; *Modified full analysis set excluded one patient from the 16-week + RBV arm who withdrew from the study after taking 3 doses of study medication. Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

59

Baseline NS5A or NS3 RASs

•  RASs at NS3 position Q80K detected in 33 of 93 patients (35%) •  One patient in the 16 week + RBV treatment group had an NS3 RAS at the 168 position

–  No patients had NS3 RASs at the 156 position

84

41 39

4

65 55

0

20

40

60

80

100

At least one NS5A

One NS5A Two NS5A Three or more NS5A

At least 1 NS3

Dual NS5A & NS3

% o

f Pat

ient

s

Number of RASs per Patient

78 93

38 93

36 93

60 93

51 93

4/93

*RASs detected by next-generation sequencing with 15% sensitivity; NS5A RAS: any change from wild-type at 4 positions (28, 30, 31, or 93); NS3 RASs = any change from wild-type at 14 positions (36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175). Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

60

Summary •  Grazoprevir (GZR)/ruzasvir (RZR)/uprifosbuvir (UPR) ± ribavirin (RBV)

was highly effective in GT1 patients who previously failed an NS5A inhibitor-containing direct-acting antiviral regimen

–  Cirrhosis had no impact on efficacy

•  16 weeks of GZR/RZR/UPR + RBV resulted in SVR12 rate of 98% (43/44).

–  One patient withdrew from the study after receiving 3 doses of study medication

•  24 weeks of GZR/RZR/UPR alone resulted in SVR12 rate of 100% (49/49)

•  High efficacy was observed despite a high prevalence of baseline NS3 and NS5A RASs in this population

•  Treatment was generally safe and well tolerated

Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

61

Abstract LBO-03

MAGELLAN-2: Safety and Efficacy of Glecaprevir/Pibrentasvir in Liver or Renal Transplant Adults with Chronic Hepatitis C

Genotype 1-6 Infection Nancy Reau1, Paul Y. Kwo2, Susan Rhee3, Robert S. Brown, Jr.4, Kosh Agarwal5, Peter Angus6, Ed Gane7, Jia-Horng Kao8, Parvez S.

Mantry9, K. Rajender Reddy10, Tram T. Tran11, Yiran B. Hu3, Abhishek Gulati3, Preethi Krishnan3, Emily O. Dumas3, Nancy S. Shulman3, Roger Trinh3, Xavier Forns12

1.  Rush University Medical Center, Chicago, IL, USA 2.  Stanford University School of Medicine, Palo Alto, CA, USA 3.  AbbVie Inc., North Chicago, IL, USA 4.  Weill Cornell Medical College, Center for Liver Disease and

Transplantation, New York, NY, USA 5.  Institute of Liver Studies, King's College Hospital NHS

Foundation Trust, London, UK 6.  University of Melbourne, Melbourne Australia

7.  University of Auckland, Auckland, New Zealand 8.  National Taiwan University Hospital, Taipei, Taiwan 9.  The Liver Institute at Methodist Dallas, Dallas, TX, USA 10. University of Pennsylvania, Philadelphia, PA, USA 11. Cedars Sinai Medical Center, Los Angeles, CA, USA 12. Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS,

Barcelona, Spain

62


In vitro:1

•  High barrier to resistance •  Potent against common NS3 polymorphisms (e.g., positions 80, 155, and

168) and NS5A polymorphisms (e.g., positions 28, 30, 31 and 93) •  Synergistic antiviral activity







Coformulated: G/P

GLE PIB

G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg; Glecaprevir was identified by AbbVie and Enanta. Ng TI, et al. Antimicrobial Agents and Chemotherapy. 2017; Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

63

MAGELLAN-2 Study Design MAGELLAN-2 is an open label, multicenter, phase 3 study investigating the safety and efficacy of 12-week G/P treatment in adults with chronic HCV GT1-6 infection without cirrhosis who have had liver or renal transplant

Conducted in Australia, Canada, Italy, New Zealand, Puerto Rico, Spain, Taiwan, the United Kingdom and the United States

G/P (300 mg/120mg) N=100

MAGELLAN-2

Open-Label Treatment

Day 0 Week 12 Week 24 Week 48

SVR12 assessment

G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

64

Key Inclusion Criteria •  ≥18 years of age

•  BMI ≥18 kg/m2

•  Chronic HCV infection with GT 1-6 (HCV RNA >1000 IU/mL)

•  Absence of cirrhosis

•  HCV treatment–naïve (all GTs) or

•  Treatment experienced with IFN, pegIFN ± RBV, or sofosbuvir (SOF) + RBV ± pegIFN (excludes GT3 patients)

•  Single liver or kidney transplant recipient ≥ 3 months prior to screening

•  On a stable immunosuppressant regimen* based on tacrolimus, sirolimus, everolimus, mycophenolate mofetil (MMF), azathioprine, cyclosporine and/or mycophenolic acid –  Prednisone/prednisolone permitted at ≤10 mg/day

–  Cyclosporine permitted at ≤100 mg/day at time of screening†

*No dose adjustment required. †Dose could be increased to ≤400mg following approval from sponsor; restriction based on increased exposure of DAA Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

65

Baseline Demographics & Disease Characteristics Characteristic 12-week G/P

N = 100 Male, n/% 75 White race*, n/% 78 Age, median (range), n/% 60 (39 – 78) BMI, median (range), kg/m2 26.0 (17.4 – 42.5) Genotype†, n/%

1 57 2 13 3 24 4 4 5 0 6 2

HCV RNA, median (range), log10 IU/mL‡ 6.5 (4 – 7.6) Fibrosis, n/%§

F0-F1 78 F2 5 F3 14

G/P, glecaprevir/pibrentasvir; HCV, hepatitis C virus; BMI, body mass index. * Race was self-reported †Genotype determined by the Versant HCV Genotype Inno-LiPA Assay Version 2.0; ‡ HCV RNA quantified by Roche COBAS Ampliprep/TaqMan v2.0 §Data missing for 3 patients Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

66

Baseline Demographics & Disease Characteristics

Characteristic 12-week G/P N = 100

HCV treatment-experienced, n/% 34 IFN-based 32 SOF-based 1 Treatment experience pre-transplant, n/% 24 Treatment experience post-transplant, n/% 10

Liver transplant, n/% 80 Kidney transplant, n/% 20 Time since transplant, median (range), months 55.6 (4.2 – 545.3) eGFR, median (range), mL/min/1.73 m2 62.3 (28.7 – 132.2) Baseline immunosuppressant medication, n/%*

Tacrolimus 66 Mycophenolic acid 29 Cyclosporine 14 Prednisone 13 Prednisolone 10 Everolimus 7 Azathioprine 6 Sirolimus 6

IFN, interferon; SOF, sofobuvir; eGFR, estimated glomerular filtration rate. *Patients could be on multiple immunosuppresant medications; total may exceed 100 Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

67

SVR12: G/P x 12 Weeks, ITT and mITT Populations

One DAA-naïve 65 year old male with GT3a infection relapsed at PTW4; one patient LTFU

98 99

0

20

40

60

80

100

SVR12, ITT SVR12, mITT

% P

atie

nts

with

SVR

12

Sustained Virologic Response

Non-inferiority threshold

98/100 98/99

Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

68

Summary 99% of transplant patients with HCV infection treated with G/P for 12 weeks achieved SVR12

•  SVR12 rate was non-inferiority to historical standard of care (SOF + RBV) SVR12 rate

•  Achievement of SVR12 was not impacted by treatment experience or any other baseline factor

G/P was well-tolerated:

•  Discontinuations due to AEs and serious AEs related to G/P were rare

•  No discontinuations due to G/P-related AEs

•  Grade 3 laboratory abnormalities were rare

•  One mild liver transplant rejection occurred unrelated to G/P DDIs Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

69 This enduring activity is supported by educational grants from

AbbVie and Gilead Sciences, Inc.

Expert Presentation Delivered by: Seng Gee Lim, MD Teerha ... · Expert Presentation Delivered by:...

Documents

Transcript of Expert Presentation Delivered by: Seng Gee Lim, MD Teerha ... · Expert Presentation Delivered by:...