Direct Acting Antivirals: What are they? What is their place in HCV management?

Mark Sulkowski, MDAssociate Professor of Medicine

Johns Hopkins University School of Medicine

Limitations of PegIFN + Ribavirin (with or without protease inhibitors)

• Antiviral activity is host + virus genotype dependent – IL28B CC genotype > TC and TT

• Safety and tolerability risk outweighs treatment benefit for some individuals– “IFN unwilling and/or unable”

• Finite number of expert healthcare providers • Cost

Therapeutic Targets for DAAs

Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.

• Prevent viral entry– Polyclonal and monoclonal antibodies– SRB1 receptor blockers

• Prevent translation of viral RNA– NS3/4 protease inhibitors

• Inhibit HCV-RNA polymerase– Nucleoside analogue NS5B polymerase

inhibitors– Non-nucleoside analogue NS5B

polymerase inhibitors– NS5A inhibitor– Cyclophilin B inhibitors

• Viral assembly/release

Direct Acting Antivirals for Hepatitis C

Nature Reviews Drug Discovery 10, 93-94 (February 2011) | doi:10.1038/nrd3361

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

Peginterferon lambda + RBVVirologic response by IL28B Genotype in patients with HCV Genotypes 1, 4

0

n = 19 46 22 38 17 40 18 57 19 46 22 38 17 40 18 57

RVR cEVR

102030405060708090

100

Hatched bars: CT/TTSolid bars: CC

120 μg 180 μg 240 μg PegIFN-λ

180 μgPegIFN-α-2a

120 μg 180 μg 240 μg PegIFN-λ

180 μgPegIFN-α-2a

Perc

enta

ge o

f pati

ents

± 9

5% C

I

Zeuzem et al. EASL 2011

Changes in Hematologic Parameters Over Time and Hematology-associated PegIFN and RBV Dose Reductions

Hem

oglo

bin

(g/L

)Pl

atel

ets

(GI/

L)

T

otal

Neu

trop

hils

(G

I/L)

LLN

Study Week

LLN

150

140

130

120

0 6 8 10 122 4

300

250

200

150

0 6 8 10 122 4

54

21

3

0 6 8 10 122 4

LLN

PegIFN-λ 120 µg PegIFN-λ 180 µgPegIFN-λ 240 µg PegIFN-α-2a

PegIFN-λPegIFN

α-2a

Lab Toxicity, %120 µg(N=128)

180 µg(N=131)

240 µg(N=134)

180 µg(N=133)

Hemoglobin low 20.5 15.4 12.9 43.9

RBV dose reduction, % (due to Hb abnormality)

2.3 1.5 0.7 12.8

Neutrophils Low 0 0.8 0 15.2Platelets Low 0 0 0 14.4

PegIFN dose reduction, % (due to hematologic abnormality)

0 0 0 17.3

Zeuzem et al EASL 2011

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

PILLAR Study: TMC435 + PegIFN/RBV

Fried et al. AASLD 2010

TMC 12/ PR24

75 mg(n=77)

TMC 24/PR24

75 mg(n=75)

TMC 12/ PR24

150 mg(n=76)

TMC 24/PR24

150 mg(n=75)

Pbo 24/PR48

(n=75)

TMC 12/ PR24

75 mg(n=78)

TMC 24/PR24

75 mg(n=73)

TMC 12/ PR24

150 mg(n=77)

TMC 24/PR24

150 mg(n=77)

Pbo 24/PR48

(n=74)

0

20

40

60

80

100

77 68 76 79

5

91 96 94 97

58

10 2016 17

11

2 1 3

11

<25 IU/mL undetectable <25 IU/mL detectable >25 IU/ml

Week 4 Week 12*** *** *** *** *** *** *** ***

PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12

Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

PILLAR Study: Role of IL28B GenotypePILLAR Week 24 Analysis: Mean Change in HCV RNA

from Baseline According to IL28B Genotype*

Mea

n(+/

- SE)

Cha

nge

in P

lasm

a H

CV R

NA

(log 10

IU/m

L) fr

om B

asel

ine CC

CTTT

Placebo

4 8 16 240

0

-2

-4

-6

Week12 20

All TMC 435 (75 mg)

Week

0

-2

-4

-64 8 16 240 12 20

All TMC 435 (150 mg)

Week

0

-2

-4

-64 8 16 240 12 20

Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

Fried et al. AASLD 2010

SILEN-C1: BI-1335 + PegIFN/RBV with or without 3-day lead-in

eRVR SVR Relapse0

20

40

60

80

100

15

55

24

8071

9

7873

15

8883

8

PR BI1335 120 mg LIBI1335 240 mg LI BI1335 240 mg No LI

Sulkowski et al. EASL 2011

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

Mericitabine + PegIFN/RBV for HCV genotype 1 patients

0 2 4 6 8 10 120%

20%

40%

60%

80%

100%

39%

83%62%

68%

62%

88%

62%80%

18%

49%

A: 500mg BID+ P/R 12 wk (n=80)B: 1000mg BID+ P/R 8 wk (n=81)C: 1000mg BID+ P/R 12 wk (n=82)D: 1000mg BID+ P/R 12 wk (n=81)E: P/R 48 wk (n=84)

Study Week

% P

atien

ts w

ith

viro

logi

c re

spon

se (<

15IU

mL)

*

0

*Roche COBAS® HCV Test; LLOD = 15 IU/mLITT population, n=408

Jensen DM, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. 81.

PSI-7977 Phase 2b Study

PEG-IFN -2a + RBV

RG7128 400 mg QD+ PEG-IFN -2a + RBV

PSI-7977 200 mg QD+ PEG-IFN -2a + RBV

PEG-IFN -2a + RBVNon-RVR PEG-IFN -2a + RBV

PEG-IFN -2a + RBVNon-RVR PEG-IFN -2a + RBV

0 12 24 48Weeks

SVRFollow-Up

72

STOP

STOP

• 150 patients GT-1, 2 & 3, treatment-naïve– Response-guided– IL28B stratified (GT-1, 125 patients)

• Primary efficacy endpoint : Safety and tolerability

PSI-7977 400 mg QD+ PEG-IFN -2a + RBV

SVRFollow-Up

GT-1 treatment-naïve

GT-2/3 treatment-naïve open-label

N=50

N=50

N=25

N=25 “12+0”

Lalezari et al. EASL 2011

PSI-7977 + PegIFN + RBV

Series10

20

40

60

80

100 98

19

Week 4

PSI7977 200 or 400 mg/P/RPR

• 121 patients with HCV genotype 1– 41% IL28B CC

• No viral breakthrough observed

• No safety signal detected

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

M Gao et al. Nature 000, 1-5 (2010) doi:10.1038/nature08960

BMS-790052 Replication Complex Inhibitor:Change in HCV RNA after administration of single dose

NS5A replication complex inhibitor + PegIFN/RBV

PR (n=12) NS5A 1 mg (n=12) NS5A 10 mg (n=12) NS5A 60 mg (n=12)0

20

40

60

80

100

25

42

9283

SVR

Pol et al. EASL 2011

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

Alisporivir (DEB025): Oral cyclophilin B inhibitor

• Synthesized from cyclosporin A– No immunosuppressive

activity; Potent Cyp inhibition

• Active all HCV genotypes• In vitro resistance in the

NS5A region• Also active against HIV

Flisiak et al. Hepatology. 2009 May;49(5):1460-8.

Alisporivir + PegIFN/RBV in HCV genotype 1, treatment naïve patients

PR APV 48 wks APV 24 wks RGT0

20

40

60

80

55

76

53

69

SVR

Flisiak R et al. EASL 2011

New Targets

• Peginterferon lambda (PegIL-29)• Protease inhibitors • Polymerase inhibitors• NS5A inhibitors • Cyclophilin inhibitors• DAA Combinations

INFORM-1: RG7128 + RG7227

• 1st clinical trial to investigate the combination of DAA in the absence of interferon and ribavirin

• Assessed safety and antiviral activity of RG7128 + RG7227 x13d• Rx-naïve, null and relapser GT-1 HCV patients (N ~90)• No evidence of resistance breakthrough in any cohort

Gane et al. The Lancet 15 Oct 2010

Telaprevir + VX-222 with or with PegIFN/RBV

TLV + 222 low

TLV + 222 high

QUAD low

QUAD high

0

20

40

60

80

100

17

59

86 87

RVR

TLV + 222 low

TLV + 222 high

QUAD low

QUAD high

0

20

40

17

31

0 0

Breakthrough

SOUND C-1: PI (1335) + non-nucleoside polymerase (7127) + RBV

Day 8 Day 15 Day 22 Day 29

Group 1:7127 (400 mg TID) +

1335 + RBV(N=15)

27% 40% 67% 73%

Group 2:7127 (600 mg TID) +

1335 + RBV(N=17)

18% 82% 100% 100%

HCV RNA < 25 IU/mL, undetectable

Two genotype 1a patients in the low dose group had viral rebound during treatment

Zeuzem S., et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-7.

PI + NS5A inhibitor ± PegIFN/RBV in prior null responder

0 1 2 3 4 5 6 7 8 9 10 11 120

1

2

3

4

5

6

7

8

Group A: No PegIFN/RBV, n = 11

Week

Log1

0 H

CV R

NA

↓ Indicates Initiation of PegIFN/RBV↓

↓

↓

LOQ 26 IU/mL LOD < 10 IU/mL

0 1 2 3 4 5 6 7 8 9 10 11 120

1

2

3

4

5

6

7

8

Group B: PegIFN/RBV, n =10

Week

Log1

0 H

CV R

NA

LOQ 26 IU/mL LOD < 10 IU/mL

LOQ LOD

LOQ LOD

Lok AS, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-8.

PI + NS5A inhibitor ± PegIFN/RBV in prior null responder

• No PegIFN/RBV– 4/11 patients had SVR-12 with no PegIFN/RBV

• 1a, 2/3 SVR with 1 relapse; 1b; 2/2

– 6/11 patients had breakthrough with PegIFN/RBV added 4 achieve undetectable HCV RNA (treatment ongoing)

• QUAD therapy (PegIFN/RBV)– 10/10 patients had SVR-12

Lok AS, et al. EASL; Berlin, Germany 2011

Future HCV therapies

• Multiple agents in phase 2 or later development – Effective across viral genotypes and subtypes– Different resistant variants – Improved safety and tolerability – Oral (with the exception of IFN λ)– Less frequent dosing

• Increase HCV treatment rates with IFN alfa free regimens