Athens, March 24th 2018

Optimal current treatment of hepatitis C

Pr Christophe Hézode, Henri Mondor Hospital, Paris-Est University, Créteil, France

Links of interest

Adviser, speaker, investigator for:

Abbvie, BMS, Gilead, Janssen, MSD

Optimal HCV treatment

✓High efficacy (SVR > 95%)

✓High level of evidence

✓ Ribavirin free

✓ Very good safety profile

✓Oral treatment

✓ Easy to take

✓ Limited DDIs

✓ Pangenotypic

Optimal but non pangenotypic options

SOFOSBUVIRNucleotide NS5B

Polymerase Inhibitor

LEDIPASVIRNS5A Inhibitor

- Pangenotypic antiviral activity

- High barrier to resistance

Antiviral activity on genotypes 1, 4, 5, and 6

Non pangenotypic combination

Once-daily, oral fixed-dose combination tablet

Real-world cohorts support ION-3 clinical trial data in >6000 GT1 patients

Kowdley KV, et al. N Engl J Med 2014;370:1879-88; Buggisch P, et al. J Hepatol 2018, in press

0

20

40

60

80

100

0

20

40

60

80

100

8 weeks

12 weeks

LDV/SOF for 8 weeks in naïve non-cirrhotic GT1 patients

97 98.6 97.8 98.7 98

ION-3 German Hepatitis C-Registry (DHC-R)

119/123 707/717 311/316 739/749 389/397

ION-3 criteria* ION-3 criteria* SmPC criteria**

*TN, NC, VL<6 millions**TN, NC

ELBASVIRNS5A Inhibitor

GRAZOPREVIRProtease Inhibitor

Antiviral activity against GT1 and GT4 including most RASs

Negligible renal elimination

No food effect

Once-daily, oral fixed-dose (50/100 mg) combination tablet

Non pangenotypic combination

Efficacy of grazoprevir/elbasvir for 12 weeks in selected groups of patients

0

20

40

60

80

100

GRZ/EBR 12 semaines GRZ/EBR 12 semaines GRZ/EBR 12 semaines

98.6 99.396.0

SVR

12

(%

)

12 weeks

GT1b

Compensated

disease

12 weeks

GT1a

HCV RNA ≤0.8 M

Compensated

disease

12 weeks

GT4

Naïve

Compensated

disease

Zeuzem S, et al. AASLD 2016, Abs 874; Oliveira A, et al, EASL 2017, Abs THU-228; Asselah T, et al. Liver Int 2018

1040/1055 135/136 97/101

C-SURFER: EBR + GZR for 12 weeks in GT1 patients with stage 4-5 chronic kidney disease

Roth D et al. Lancet 2015;386:1537-45

First controlled study in patients with renal insufficiency treated with DAAs•

Stratification according to diabetes (• 3̴5%) and hemodialysis ( 7̴5%) status

Efficacy of EBR/GZR in patients with chronic HCV infection and inherited blood disorders

Hezode C et al, Hepatology 2017;66:736-45

SVR12 in the immediate treatment group (FAS)

Study design

*Compensated liver disease

Combinations Patients Patients Patients Patients

Sofosbuvir/Ledipasvir8 weeks

Genotype 1Naïve

No cirrhosis- -

Grazoprevir/Elbasvir12 weeks

Genotype 1b* Genotype 1a*VL <800.000

Genotype 4*Naïve

Severe CKD*(GFR<30)

Genotype 1

Summary for non pangenotypic options

Optimal and pangenotypic options

SOFOSBUVIRNucleotide NS5B

Polymerase Inhibitor

VELPATASVIRNS5A Inhibitor

- Pangenotypic antiviral activity

- High barrier to resistance

Pangenotypic antiviral activity including most RASs

Once-daily, oral fixed-dose(400/100 mg) combination tablet

Pangenotypic combination

28/28 25/27

Phase 2 data: SOF/VEL 8-Week treatment duration in treatment-naïve genotype 1 patients without cirrhosis

SVR

12

(%

)

3 relapses1 D/C for AE

5 relapses 3 relapses 5 relapses1 LTFU

28/28 25/27

26/30

25‒

25/30 26/29 25/31

25+

100‒

100+

VEL, mg

RBV

Everson G et al. Ann Intern Med 2015

ASTRAL-1, -2, -3: SOF/VEL for 12 weeks in GT1–6 treatment-naive and -experienced* patients with and without cirrhosis

D/C, discontinued; LTFU, lost to follow-up.* Patients treated with pegIFN/RBV ± PI or IFN ± RBV. Feld JJ, et al. N Engl J Med 2015;373:2599–607

Foster GR, et al. N Engl J Med 2015;373:2608–17

98 99 100 97 10095

0

20

40

60

80

100

GT1 GT2 GT4 GT5 GT6 GT3

nN

323328

237238

116116

4141

3435

264277

12 weeks

ASTRAL-3 ASTRAL-1 & -2

SVR

12

(%

)

2 relapse1 D/C2 LTFU

1 D/C 1 death11 relapse

2 LTFU

*

0

20

40

60

80

100

No NS5A RAS NS5A RAS notY93H

Y93H

98 97

86

411/420 33/34 19/22

SVR

12

(%

)

Impact of NS5A RAS on efficacy of SOF + VEL for 12 weeks in DAA-naïve GT3 patients (pooled ASTRAL-POLARIS analysis)

Hezode C, et al. J Hepatol 2017, Dec 5

HCV GT Patients, N SVR % (n/N) HCV Subtype Patients, n SVR % (n/n)

1 694 99.0% (687/694)

1a 484 98.9% (479/484)

1b 206 99.5% (205/206)

1e 1 100.0% (1/1)

1h 1 100.0% (1/1)

1novel or mixed 2 (1/2)

2 316 100.0% (316/316)

2a 60 100.0% (60/60)

2b 192 100.0% (192/192)

2c 18 100.0% (18/18)

2d 2 (2/2)

2e 1 (1/1)

2i 9 (9/9)

2j 1 (1/1)

2k 5 100.0% (5/5)

2 novel or mixed 9 100.0% (9/9)

3 478 97.5% (466/478)

3a 472 97.5% (460/472)

3b 3 (3/3)

3g 2 (2/2)

3k 1 (1/1)

HCV Genotype and subtype and treatment outcome to SOF/VEL (pooled ASTRAL-POLARIS)

.

Hezode C, et al. J Hepatol 2017, Dec 5

• Hézode C, et al. J Hepatol 2017, Dec 5HCV GT Patients, N SVR % (n/N) HCV Subtype Patients, n SVR % (n/n)

4 197 99.5% (196/197)

4a113 99.1% (112/113)

4b 2 (2/2)

4c 2 (2/2)

4d41 100.0% (41/41)

4f 3 (3/3)

4g 1 (1/1)

4k 5 100.0% (5/5)

4n 7 100.0% (7/7)

4o 8 100.0% (8/8)

4r 3 (3/3)

4t 1 (1/1)

4 novel or mixed 11 100.0% (11/11)

HCV Genotype and subtype and treatment outcome to SOF/VEL (pooled ASTRAL-POLARIS)

Hezode C, et al. J Hepatol 2017, Dec 5

8388

50

10094 96 85 100

86

92

50

86

0

20

40

60

80

100

Overall GT1 GT3 GT 2, 4, and 6

SVR

12

(%

)

SOF/VEL 12 wk SOF/VEL+RBV 12 wk SOF/VEL 24 wk

SOF/VEL + RBV resulted in highest SVR12 in patients with decompensated liver disease

75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4GT4 4/4

GT2 4/4GT4 2/2

GT2 3/4GT4 2/2GT6 1/1

Sofosbuvir, velpatasvir and ribavirin in patients with decompensated cirrhosis

Curry MP, et al. N Engl J Med 2015;373:2618–28

SOFOSBUVIRNucleotide NS5B

Polymerase Inhibitor

VELPATASVIRNS5A Inhibitor

Pangenotypic antiviral activity including most RASs

Pangenotypic combination

VOXILAPREVIRNS3 Protease Inhibitor

6 patients with relapse (1 GT1a, 4 GT3 et 1 GT4)

97 96 100 100 95 91100 100

0

20

40

60

80

100

GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6

4545

2022

7478

66

97101

55

11

146150

GT1a GT2 GT3 GT4 GT5 GT6GT1bGT1

SVR

12

(%

)

SVR12 according to genotype

POLARIS-1: Sofosbuvir/velpastasvir/voxilaprevirfor 12 weeks in DAA-experienced patients with 1st

generation NS5A inhibitor

Bourlière M, et al. N Engl J Med 2017;376:2134-46

PIBRENTASVIRNS5A Inhibitor

GLECAPREVIRNS3 Protease

Inhibitor

Pangenotypicantiviral activity including most RASs

High barrier to resistance

Negligible renal elimination

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

Pangenotypic combination

Integrated efficacy analysis: G/P for 8 Weeks in GT1–6 treatment-naive and -experienced* patients without cirrhosis

• BT, breakthrough; mITT, modified intent-to-treat.* Includes patients with prior SOF use (8-week G/P, n = 7); † One GT6 patient initially with missing SVR12 data is excluded from this analysis; ‡ All GT3 patients were treatment naive. Bernstein D, et al. ACG 2017 (oral presentation)

98 99 98 95 95100 10099 99 99 97 100 100 100

0

20

40

60

80

100

Overall GT1 GT2 GT3 GT4 GT5 GT6

mIT

T, S

VR

12

(%

)

‡

470471

202204

198204

5959

22

12†

12943†

952nN

2 BT

7 RL

5 D/C

7 LTFU

470474

202205

198208

5962

22

1313

944965

1 BT

2 D/C

1 LTFU

2 RL

2 D/C

1 BT

5 RL

4 LTFU

1 D/C

2 LTFU

ITT mITT

Integrated efficacy analysis: G/P for 12 weeks in GT1–6 treatment-naive patients with cirrhosis

Krishnan P, et al. J Hepatol 2017; 66(Suppl):S500 (poster presentation FRI-205)

98 97 100 99 100

0

20

40

60

80

100

Overall GT1 GT2 GT3 GT4–6

ITT,

SV

R1

2 (

%)

119126

6971

2626

6465

22

2020

179182

nN

SURVEYOR-II, Part 3: G/P for 12 or 16 weeks in GT3 patients with prior treatment failure and/or cirrhosis

• *Includes SOF-experienced patients Wyles DL, et al. AASLD 2016

9196 98 96

0

20

40

60

80

100

1 2 3 4

SVR

12

(%

)

TE*Non-cirrhotic

12 weeks

TE*Non-cirrhotic

16 weeks

TNCirrhotic12 weeks

TE*Cirrhotic16 weeks

2 relapses 1 relapse 1 LTFU1 breakthrough

1 relapse

2022

2122

3940

4547

nN

Efficacy

Pol S, et al. EASL 2017: SAT27* mITT was not reported in this analysis.

98 98 98 97 98

0

20

40

60

80

100

Overall CKD1 CKD2 CKD3 CKD4-5

SVR

12

(%

) -

mIT

T

nN

21882238

10241045

3536

101103

10281054

No impact of the grade of renal insufficiency on Glecaprevir / Pibrentasvir efficacy

Naïve / Treatment-experiencedŦ

Ŧ Naive and treatment-experienced patients for GT1,2,4,5,6

Glecaprevir/pibrentasvir in patients with kidney disease

MAGELLAN: Glecaprevir/pibrentasvir (G/P)in DAA-experienced patients

Poordad F, et al. Hepatology 2017, Nov 20

weeks

SVR12

0 12 24

G/P

20

n = 44 (43 GT1, 1 GT4)

12 weeks

SVR12G/P

16 28

n = 47 (43 GT1, 3 GT4)

16 weeks

Ran

do

mis

atio

n1

:1

0

20

40

60

80

100

SVR

12

, %

12 weeks

89

16 weeks

91

3944

4347

1 (2 %) 4 (9 %)

4 (9 %) 0

Breakthrough

Relapsee

Impact of baseline RASs

0

20

40

60

80

100

RV

S12

, % p

atie

nts

None

1313

NS3alone

22

45

1313

G/P - 12 weeks G/P - 16 weeks

BaselineRAS

2024

2223

NS5Aalone

100 80 100 2583 96100 100

44

14

3 relapses 1relapse

NS3 +NS5A

None NS3alone

NS5Aalone

NS3 +NS5A

Patients GlecaprevirPibrentasvir

SofosbuvirVelpatasvir

No cirrhosisAll genotypes

8 weeks* 12 weeks

Compensated cirrhosis All genotypes

12 weeks* 12 weeks

Peg-IFN/RBV experiencedGenotype 3

No 12 weeks

Severe CKD (GFR <30 ml/mn)All genotypes

8-12 weeks No

Child-Pugh B7-9 cirrhosisAll genotypes

No + RBV 12 weeks

1st generation DAA failureAll genotypes

No + Voxilaprevir12 weeks

Summary for pangenotypic options

*Except GT3 PR treatment-experienced

Thank you very much for your attention