DAA’s in phase III,

the near future in IFN free regimen

12 june 2014

Pr Philippe Halfon, MD, PhD

Hôpital Europeen

Marseille, France

1 Introduction

2 Viral Cycle and DAAs

3 DAAs in Phase III

4 Special focus on HCV-G4

5 Conclusion

DAA’s in phase III,

the near future in IFN free regimen

Disclosures Philippe Halfon

– Speaker for : Roche, Merck, Janssen, Gilead, BMS

– Boardmember : Provepharm, SoulPharma

– Shareholder and Founder: Genoscience

Drug targets in the HCV lifecycle

RNA replication

Nucleocapsid

assembly

Core of the

virus released RNA uncoating

Translation

&

polyprotein

processing RNA synthesis

Liver cell

Transport and release

miR-122 inhibitor

(LNA)

Protease

inhibitors

NS5A

inhibitors

CD81 Receptors

NS5A

inhibitors

Early

inhibitors

NS5B

polymerase

inhibitors New Therapies & Targets

Life Cycle Step

Cyclophilin

inhibitors

Capsid RNA

Polymerase

Metalloprotease

Serine protease

RNA helicase

Envelope

Glycoproteins

E1 C E2

Nonstructural proteins Structural proteins 5’NTR 3’NTR

NS1 NS2 NS3 NS4A NS4B

Cofactors

NS5A NS5B

Protease Inhibitors

Telaprevir

Boceprevir

Simeprevir

Faldaprevir

Asunaprevir

ABT-450

MK-5172

Sovaprevir

ACH-2684

NS5A Inhibitors

Daclatasvir

Ledipasvir

ABT-267

GS-5816

ACH-3102

PPI-668

GSK-2336805

Samatasvir

MK-8742

Polymerase Inhibitors

Nucs Non-Nucs

Sofosbuvir ABT-333

VX-135 Deleobuvir

IDX-20963 BMS-791325

ACH-3422 PPI-383

GS-9669

TMC-647055

Direct-acting antivirals (DAAs)

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014

Triple Therapy:

1 DAA + PegIFN alfa/RBV IFN-Free Regimens (phase III)

Simeprevir (PI)

Faldaprevir (PI)

Sofosbuvir (NI)

Daclatasvir (NS5A)

MK 5172 (PI)

Danoprevir (PI)

Alisporivir (CYP)

Sofosbuvir + RBV

Sofosbuvir + GS-5885 ± RBV

ABT-450/RTV + ABT-267 ± ABT-333 ± RBV

Daclatasvir + Asunaprevir

Investigational HCV Regimens in Phase II & III Trials in 2014

Asselah and Marcellin P,. Liver International 2014

IFN-Free Regimens (phase II)

Simeprevir + Sofosbuvir

Daclatasvir + Sofosbuvir

Daclatasvir + Asunapreivr + BMS 791325

MK 5172 + MK 8742 ± RBV

PI,

1st Generation PI,

2nd Generation

NS5A Inhibitors

1st Generation

NS5A Inhibitors

2nd Generation

NS5B

Nucleoside

Inhibitors

NS5B

Non-Nucleoside

Inhibitors

Efficacy

Resistance

Profile

Pangenotypic

Efficacy

Adverse

events

Drug-drug

interactions

Good profile Average profile Least favorable profile

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013

General Characteristics of Direct-Acting Antivirals

CHINA 30M

INDIA

18M

USA 5M

RUSSIA 6M

JAPAN

3M EGYPT

12M

PAKISTAN

9M

BRAZIL

4M

INDONESIA

9M

NIGERIA

3M

DR CONGO

4M

CAMEROON 3M

HCV worldwide: Limited access to new treatment options

in countries with the highest HCV prevalence

Asselah T et al. Liver International 2014, in press

Mylan, Sun Pharma and Dr Reddy : are negociating with

Gilead for a production of a generic of Sofosbuvir :

Objective price : 130 USD

Improved HCV treatments continue to be approved in 2014

Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec

Telaprevir

Boceprevir

Interferon Free

Triple therapy

Sofosbuvir

(G1,4,5,6)

Sofosbuvir

+

RBV

G2/3

Daclatasvir*

(G1, 2, 3, 4)

2011 2012 2013 2014 2015

IFN

-fre

e

IFN

-ba

se

d

Simeprevir*

(G1, 4)

European approvals

Protease inhibitor

Nuc inhibitors

NS5A

NS5B inhibitor

Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor

*Not yet approved in Europe

Current access to second-generation DAAs in Europe 2014

Sofosbuvir Simeprevir

DCV Asunaprevir

Sofosbuvir

Sofosbuvir

Sofosbuvir

Potency

Genotype Coverage

Resistance Barrier

Safety/Tolerability

Half life & Pills burden

Treatment Duration

Drug-drug Interaction

Highest Importance

Secondary Priorities

Cost

Priorities for Direct-Acting Antivirals

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013

DAA’s in phase III,

the near future in IFN free regimen

1 Introduction

2 Viral Cycle and DAAs

3 DAAs in Phase III

4 Special focus on HCV-G4

5 Conclusion

12 12 12/24 12 12/24 24 12/24 12

24/48 24/48 24/48 12 24/48 24 12/24 12

Current options for genotype 1 treatment-naïve patients

Cross comparison of studies cannot be carried out Q8h, every 8 hours; bid, twice daily *Not yet approved in Europe; ‡duration in weeks ¶F4 excluding non-VF failures

1. Buti M, et al. Gastroenterology 2014;146:744–53; 2. Jacobson I, et al. AASLD 2013. Abstract

1122

3. Jensen D, et al. AASLD 2013. Abstract 1088; 4. Lawitz E, et al. N Engl J Med 2013;368:1878–87

5. Hézode C, et al. AASLD 2012. Abstract 755; 6. Sofosbuvir EU SmPC

7. Lawitz E, et al. EASL 2014. Abstract O165; 8. Sulkowski M, et al. NEJM 2014;370:211‒21

TVR/PR

(bid)

SMV*/PR FDV*

240 mg/PR

SOF/PR DCV*

60 mg/PR

OPTIMIZE1 NEUTRINO4 Pooled

QUEST1 & 22 COMMAND-15 STARTVerso

1&23

295/

327

274/

369

419/

521

378/

524

94/

146

16/

17 104/

159

QUANTUM &

NIAID Study

11-I-02586

COSMOS7

SV

R (

%)

SOF/RBV SOF/SMV*

±RBV¶

DAA

duration‡

Treatment

duration‡

41/

41

SOF + DCV

A14440408

Current and near future options for genotype 1 treatment-experienced patients

Cross comparison of studies cannot be carried out *Not yet approved in Europe ‡Excluding non-virologic failures ¶These data are from Japanese patients

1. Forns X, et al. Gastroenterology 2014. [Epub ahead of print] 2. Reddy K, et al. APASL 2014; 3. Jacobson I, et al. AASLD 2013. Abstract 1100

4. Suzuki F, et al. APASL 2012; 5. Lawitz E, et al. EASL 2014. Abstract

O165

Some data

on re-

treatment

with

SOF/PR, but

no Phase II

or III data

available 101/

145

102/

234

206/

260

69/

99

33/

57

48/

145 3/9 21/

22

Relapsers Partial

responders Nulls Non

responders Relapsers Partial

responders Nulls Nulls

SMV 150mg*/

SOF 400mg*

±RBV‡

SMV

150 mg*/PR

SMV

150 mg*/PR

FDV* 240mg/PR (12 week arm) DCV

60 mg*/PR¶

PROMISE1 ATTAIN2 STARTVerso-33 COSMOS5 COMMAND-24

DAA

duration‡

Treatment

duration‡

12 12 12/24 24 12/24

24/48 48 24/48 24/48 12/24

COSMOS cohort 2: no impact of RBV on SVR12

Excludes non-virologic failures Lawitz E, et al. EASL 2014. Abstract O165

Q80K METAVIR F4

METAVIR F4

Null responders

SV

R1

2 (

%)

11/

11

24 weeks

12/

12

10/

11

9/

9

6/

7

9/

9

4/

5

4/

4

4/

4

12 weeks

13/

14

11/

11

7/

8

7/

7

7/

8

4/

4

3/

3

SMV/SOF/RBV SMV/SOF

Without With Q80K

Without With Q80K

Potency of new therapies in patients who have previously failed treatment with First

generation DAAs

Sulkowski MS, et al. N Engl J Med 2014;370:211–21

SOF + DCV*

24 weeks

20/21

RBV – +

SV

R1

2 (

%)

21/21

No cirrhosis

Sofosbuvir + R

12 weeks

SVR

97% G2 Naive

Sofosbuvir + R

12 weeks 93% G2 IFN intolerant / Ineligible

Sofosbuvir + R

12/16 w

86% / 94% G2 NR

60%/ 78% G2 NR cirrhotic

Lawitz E et al. N Engl J Med. 2013;368(20):1878-1887

Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877

Zeuzem S et al. Hepatology AASLD 2013 : Abst 1085

Genotype 2 patients

100

91

50

63

0

20

40

60

80

100

Genotype2 Genotype3

SOF+PEG/RBV12weeks.

SOF/RBV24weeks.

HC

V R

NA

< L

LQ (

%)

Esteban R, Espagne, EASL 2014, Abs. O8 actualisé

Sofosbuvir + R

12 weeks

SVR

56% G3 Naive

Sofosbuvir + R

12 weeks 61% G3 IFN intolerant / Ineligible

Sofosbuvir + R

12/16 w

30% / 62% G3 NR

19% /61% G3 NR cirrhotic

Lawitz E et al. N Engl J Med. 2013;368(20):1878-1887

Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877

Zeuzem S et al. Hepatology AASLD 2013 : Abst 1085

Genotype 3

Sofosbuvir + R

24 weeks

93% G3 NR

92% (12/13) G3 Naive cirrhotic

60% (27/45) G3 NR cirrhotic

SVR according to fibrosis in GT-3 patients

Patients G3 : retreatment with sofosbuvir after sofosbuvir failure*

93

74

88

47

0

20

40

60

80

100

SOF+PEG/RBV12weeks. SOF+RBV24weeks.

Nocirrhosis Cirrhosis

13/14 7/8 17/23 7/15

HC

V R

NA

< L

LQ (

%)

Esteban R, Espagne, EASL 2014, Abs. O8 actualisé

n = 16 14 14 16 14 14 16 14 14 16 14 14 16 14 14

Week 4 EOT SVR4 SVR12 SVR24

Sofosbuvir* lead-In +

daclatasvir*

Daclatasvir +

sofosbuvir

Daclatasvir +

sofosbuvir + RBV

Missing

88

93

GT2/3 patients: effective IFN-free regimens in treatment-naive patients

Sulkowski MS, et al. AASLD 2012, oral LB-2. Available at: www.clinicaloptions.com/Hepatitis/Conference%20Coverage/

AASLD%202012/Conference%20Track/Capsules/LB2.aspx. [Accessed July 2013].

94

88 88

86 86

* Investigational compound not licensed in Europe.

EOT, end of treatment; LOD, limit of detection

Ruane Pj et al. J Hepatol 2014 EASL 2014 Absst 1243

Genotype 4

Sofosbuvir + R

12/24

weeks

79% / 59% G4 Naive/ NR 12w

100% / 87% G4 Naive/ NR 24 w

Daclatasvir + +/- RBV

12 weeks Sofosbuvir

Simeprevir + 12 weeks +/- RBV

Sofosbuvir

Improved HCV treatments continue to be developed

Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec

Telaprevir

Boceprevir

Interferon Free

Triple therapy

Faldaprevir*

(G1)

Sofosbuvir

(G1,4,5,6)

Sofosbuvir

+

RBV

G2/3 +

Asunaprevir*

Daclatasvir*

±

BMS-325*

Daclatasvir*

(G1, 2, 3, 4)

Sofosbuvir+

Ledipasvir

FDC*

Ombitasvir*

Dasabuvir*

+

ABT-450*/r

RBV

+

±

2011 2012 2013 2014 2015

IFN

-fre

e

IFN

-ba

se

d

Simeprevir*

(G1, 4)

European approvals

RBV

±

Protease inhibitor

Nuc inhibitors

NS5A

NS5B inhibitor

Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor

*Not yet approved in Europe

Sofosbuvir/Ledipasvir + RBV in GT-1 patients

High efficacy with 12 weeks without Ribavirin. 1 Mangia A, et al. EASL 2014, Abs. O164.

2Afdhal N, et al. EASL 2014, Abs. O109. 3 Kowdley KV, et al. EASL 2014, Abs. O56 .

ION-1 1

12 vs 24 weeks. G1 naive (865pts)

ION-2 2

12 vs 24 weeks. Trt experienced G1 (440 pts)

ION-3 3

8 vs 12 sem. G1 naive non cirrhotics (647pts)

98 %

99 %

99 %

97 %

99 %

99 %

94 %

96 %

94 %

93 %

SVR 12

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

0 8 12 24 weeks.

95 %

C-WORTHY : 2 DAA for 12 weeks

SVR 4-12

Population Fibrosis MK-5172 + MK-8742

+ RBV

MK-5172 + MK-8742 + 12 w.

(between 12-18)

Naive co-infected Non cirrhotic 97 % (28/29) 90 % (26/29)

Naive Non cirrhotic 94 % (80/85) 98 % (43/44)

Naive Cirrhotic 90 % (28/31) 97 % (28/29)

Null Responder Cirrhotic

Non cirrhotic 94 % (30/32)* 91 % (30/33)*

Hézode C, Créteil, EASL 2014, Abs. O10. Lawitz E, Etats-Unis, EASL 2014, Abs. O61. Sulkowski M, Etats-Unis, EASL 2014, Abs. O63.

* Among cirrhotic patients 44/46 (96 %)

3 DAA: ABT450/r, ombitasvir (ABT 267) and dasabuvir (ABT 333) For 12 weeks in GT-1 patients

SAPPHIRE-I (12 weeks)

PEARL-II (12 weeks)

TURQUOISE-II (12 & 24 weeks)

SAPPHIRE-II (12 weeks)

PEARL-III (12 weeks)

PEARL-IV

(12 weeks)

STUDY

3DAA + RBV (n = 473)

3DAA + RBV (n = 88)

3DAA + RBV, 12 weeks. (n = 208)

3DAA + RBV (n = 297)

3DAA + RBV (n = 210)

3DAA + RBV (n = 100)

Treatment

3DAA (n = 91)

3DAA (n = 209)

3DAA (n = 205)

3DAA + RBV, 24 weeks. (n = 172)

GT1 with compensated cirrhosis , naïve and Treatment-experienced (n = 380)

Treatment naive (n = 631)

Treatment-experienced (n = 394)

GT1b Treatment-experienced (n = 179)

GT1b Treatment naive (n = 419)

GT1a Treatment naive (n = 305)

Patients

3DAA = combination of ABT-450/ritonavir (150/100 mg) with ombitasvir (ABT-267) (25 mg) QD plus dasabuvir (ABT-333) (250 mg) TID with or without ribavirin

SVR12

96 %

96 %

96 %

100 %

99 %

97%

99 %

92 %

90%

96 %

EASL 2014

Interferon-free regimen in Naive GT-1 cirrhotic patients

Afdhal N, et al. EASL 2014, Abs. O109 Poordad F et al. EASL 2014, Abs. O163 Mangia A, et al. EASL 2014, Abs. O164 Lawitz E et al. EASL 2014, Abs. O165

SVR G1a G1b

94 100

94 100

92,2 92,9 100 100

90 97 97 97 100 100 100

66

0

20

40

60

80

100

28 31

28 29

30 31

29 30

3 3

5 5

6 6

2 3

59 64

52 56

22 22

18 18

32 34

33 33

31 33

36 36

SVR

G1a G1b

86 82

100 100 93,3

100 100 100

80

92,9 100 100

85,7

100 100 100 94 91 100 97 100 100

80

100

Relapsers or non responders bi or

tri

Relapsers bi

Partial R bi

Null R bi

Relapsers bi

Partial R bi

Null R bi

Null R bi

Null R bi

6 7

14 14

10 10

30 32

4 5

9 9

4 4

4 4

11 11

40 50

39 42

25 25

19 22

18 22

22 22

14 15

22 22

13 13

10 10

20 20

3 3

30 33

32 32

29 30

0

20

40

60

80

100

Interferon-free regimen in Treatment-experienced GT-1 cirrhotic patients

Afdhal N, et al. EASL 2014, Abs. O109 Poordad F et al. EASL 2014, Abs. O163 Mangia A, et al. EASL 2014, Abs. O164 Lawitz E et al. EASL 2014, Abs. O165

ABT-450/r (150/100 mg /d) ; ombitasvir (25 mg/d) ; RBV ( 1 000 or 1 200 mg/d)

(n = 44)

(n = 42)

(n = 49)

D1 Week 12

ABT-450/r + ombitasvir Naive

ABT-450/r + ombitasvir + RBV Naive

ABT-450/r + ombitasvir + RBV Relapsers/partial responders/nulls responders

Study design

ABT-450/r/ombitasvir + RBV For 12 weeks in GT-4 patients

• Phase II study

• 86 Naive patients, GT-4, F0-F3

• 49 Treatment failure patients, GT-4, F0-F3

Hézode C, et al. EASL 2014, Abs. O58

SVR 12

91% (40/44)

SVR 4

100% (42/42)

100% (37/37)

GS-5816 : a new pangenotypic NS5A I.

• Open label study

– SOF 400 mg + GS-5816 25 mg for12 weeks.

– SOF 400 mg + GS-5816 100 mg for12 weeks.

• Naive GT 1-6, non cirrhotic patients

Everson G, et al. EASL 2014, Abs. O111.

w24 D1 w12

SVR12

G2–6

(n = 45)

G3

(n = 54)

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

SOF + GS-5816 25 mg

SOF + GS-5816 100 mg

G1

(n = 55)

SVR 12

96 %

100 %

91 %

100 %

93 %

93 %

DAA + PR

Simeprevir

Faldaprevir

Sofosbuvir

IFN free

Sofosbuvir/ ledipasvir FDC ± RBV

ABT-450r/ABT-267 FDC + ABT-333 ±

RBV

Daclastavir + Asunaprevir

G1b

2015-2016

2014-2015

Simeprevir + Sofosbuvir

Daclatasvir

Other IFN-free combinations Other DAA + PR

Telaprevir

Boceprevir

Conclusion & Perspectives

Asselah and Marcellin P,. Liver International 2014

Daclatasvir + Sofosbuvir

MK 5172 + MK 8742 ± RBV

NS5A

+

NS5B Nuc

NS3-4/r

+

NS5B non NUC

+

≈100%

SVR

Treatment duration

12 weeks

(8-24?)

RBV +

PEG

IFN

+

HTA

+

Cure ?

HCV : yes

Liver disease : ?

< 5 %

Future

Chronic HCV infection can be cured … but challenges still remain

Older age:

polypharmacy Undiagnosed

patients

Intravenous

drug users

Advanced

disease

Coinfected

(e.g. HIV, HBV) Failing

patients

Ethnicity /

geographic

differences

Adherence

challenges?

100%

20%

10%

DIAGNOSIS

and therapy

Cure

All

HCV

patients

PEG-IFN/RBV

100%

20%

95% SVR

19%

100%

90%

85%

95% SVR

And increase of diagnosis