Non-Protease Novel Agents for Chronic Hepatitis C

Non-Protease Novel Agents for

Chronic Hepatitis C

HCV Resistance Workshop

Boston, Massachusetts

June 23, 2011

Ira Jacobson, M.D.

Vincent Astor Professor of Medicine

Chief, Division of Gastroenterology and Hepatology

Medical Director, Center for the Study of Hepatitis C

Weill Cornell Medical College New York Presbyterian Hospital

Core E1 E2 P

7

NS2 NS3 NS4A NS4B NS5A NS5B

Targets for New Hepatitis C Drugs

5– –3

Linear Telaprevir

Boceprevir

ACH-1625

GS-9256

Macrocyclic Danoprevir (RG7227)

TMC 435350

BI-201335

BMS-650032

Vaniprevir

BMS-790052

Active site

(nucleosides)

RG7128

IDX184

PSI-7977

Non-

nucleosides

ABT-333

ABT-072

GS 9190

ANA598

VCH-759

VCH-916

VX-222

Filibuvir

BI-207127

Protease

inhibitors

Polymerase

inhibitors

Cyclophilin Alisporivir

SCY-635

Not all-inclusive

Clemizole

Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA

Current Paradigms of Novel HCV Drug

Development

PEG IFN + RBV

+ New Drug

PEG IFN + RBV

+ New Drug 1

+ New Drug 2

IFN-Free

Combinations

PEG IFN + RBV

+ New Drug

PEG IFN + RBV

+ New Drug 1

+ New Drug 2

IFN-Free

Combinations

PEG IFN + RBV

+ New Drug

PEG IFN + RBV

+ New Drug 1

+ New Drug 2

Some studies include combinations of these regimens


Meracitabine (RG7128), Nucleoside Polymerase

Inhibitor, Combined With PR in Genotype 1/4

Phase IIb, treatment-naïve

Pockros P, et al. EASL 2011, Berlin, O1359

Meracitabine

1000 mg bid

+ PR (RGT based on eRVR)

PR

n=81 n=85

Interim analysis presented at EASL 2011


Meracitabine (RG7128) With PR in G1/4

0

20

40

60

80

100

RVR eRVR Week

12

Week

24

MCB/PR

PR

HCV RNA neg

% 63

14

60

13

63

14

89

61

91

62

Pockros P, et al. EASL 2011, Berlin, O1359 • Tolerability similar to PR

• No resistance


Meracitabine (RG7128) With PR in G1/4:

SVR in eRVR Group

0

20

40

60

80

100

SVR-12 Relapse

% 76

24


37/49 12/49


Meracitabine: eRVR and SVR

Association With IL28B

eRVR (%)

0

20

40

60

80

100

CC Non-CC

SVR After eRVR (%)

0

20

40

60

80

100

CC Non-CC

80

72

83

55


15/18 18/33 12/15 13/18


The relapse rate with meracitabine was

higher than reported with the protease

inhibitors. Is this a “class effect” or

related to the properties of the drug?

8 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA

PSI-7977 (Nucleoside) + PEG IFN/RBV in

Treatment Naïve Patients (PROTON Study)

125 treatment-naïve patients with HCV GT1

Planned 12 Week Interim analysis: Nelson et al. EASL LB poster #1372

Week 0 12 48 72 24

PSI-7977 200 mg QD

Peg-IFN + RBV

PSI-7977 400 mg QD

Peg-IFN + RBV Peg-IFN + RBV

Peg-IFN + RBV

SVR

Follow-Up

Peg-IFN + RBV Non-RVR Peg-IFN + RBV

STOP

Non-RVR Peg-IFN + RBV

STOP

N=50

N=50

N=25

HCV GT1

25 treatment-naïve patients with HCV GT2/3

PSI-7977 400 mg QD

Peg-IFN + RBV N=25

Week 0 12

HCV GT2/GT3

SVR24 SVR12


PROTON:

Treatment-naïve HCV GT11

RVR cEVR EOT Relapse SVR12

HCV GT1

PSI-7977 200mg QD

PEG/RBV

n=48

98% 100%

HCV GT1

PSI-7977 400mg QD

PEG/RBV

n=47

98% 92%

HCV GT1

Placebo

PEG/RBV

n=26

19% 62%

Nelson D et al, EASL LB#1372

GT1 Portion of Trial Ongoing

Response was independent of IL28B genotype


Week 2

Week 4 RVR

Week 12 cEVR/EOT

SVR12

n (evaluable) 24 24 24 24

HCV RNA < LOD 21 24 24 24

% Response 88% 100% 100% 100%

Lost to follow-up 1 1 1 1

% Response (ITT) 84% 96% 96% 96%

PROTON HCV GT2/GT3 - Antiviral Responses

24/25 enrolled subjects completed therapy

– One subject lost to follow-up after day 1

Consistent HCV RNA reduction: 24/24 RVR & cEVR(EOT)

– No difference in viral kinetics: GT 2 v GT 3; IL28B CC v T allele

No virologic breakthrough & no relapse through 12 weeks post-therapy

SVR12 in 24/24 subjects with evaluable data

Lalezeri J et al, J Hepatol 2011;54:S28



NUCLEAR: PSI-7977 + PSI-938 combination:

First purine/pyrimidine combination study

40 HCV G1 treatment-naive subjects; 8 active and 2 PBO per cohort

HCV RNA >50,000 IU/mL, no evidence of cirrhosis

All subjects offered full course of PR on Day 15

Lawitz E, et al. EASL 2011, Berlin, P1370

Cohort Day 7 Day 14 Total

< LOD Median < LOQ < LOD Median < LOD (%)

1 2 -4.5 5 4 -5.2 4/8 (50)

2 2 -4.6 8 8 -5.2 8/8 (100)

3 4 -4.7 8 7 -5.0 7/8 (88)

4 1 -4.4 8 5 -5.0 7/8 (88)

HCV RNA Δ from BL and subjects with HCV RNA <15 IU/mL (LOD)

PSI-938 300 mg QD

PSI-938 300 mg QD

PSI-7977 400 mg QD

PSI-7977 + PSI-938

PSI-7977 + PSI-938

PSI-938 + PSI-7977

Day 0 7 14

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Phase IIB Trial of Tegobuvir (Non-nuclesoide) +

PR vs PR for Chronic Genotype 1

3 arms:

–PR 48 wks (n=64)

–PR + TGV (40mg bid) 48 wks (n=126)

–PR + TGV (40mg bid) RGT (n=62)

Demographics:

–Comparable except IL28B

12% more CC in PR arm (45% CC)



HC

V R

NA

<25

IU

/mL

(%

)

No difference in AEs between triple therapy and PR


Phase IIB trial of Tegobuvir (GS9190, Non-

nucleoside) + PR vs PR for Genotype 1


Emergence and Persistence of NS5B Mutations

Following Tegobuvir

N=148 in TGV arms with BL sequencing;

– Poor response or rebound (n=17)

– Relapse (n=15)

Main mutations in NS5B: C445, Y448, Y452, C316

C316N at BL did not affect response. Y448H most abundant mutation in G1a and G1b.

C445 only seen in G1b 4/6

Persistent Y448 mutations at 1-year follow-up

Hebner C, et al. EASL 2011, Berlin, P1211

NS5B TGV mutation

Mutation at rebound in arms 2+3, % (n)

G1a (n=11) G1b (n=6)

Y448H, H/Y or H/R 91 (10) 33 (2)

C316N(BL) + Y448H 17 (1)

C316N(BL) + C445C/F + Y448H/Y

17 (1)

C445F/Y452H 33 (2)

No relevant DRMs 9 (1)

Observed NS5B mutations associated

with poor response/viral rebound


Inhibitors of Other Targets


SVR12 with BMS-790052, an NS5A inhibitor, in

Treatment-naïve G1 patients

NS5A considered a replication complex inhibitor

BMS-790052 is an NS5A inhibitor with picomolar potency against HCV replicons

Resistance barrier similar to protease inhibitors (different mutations)

4 arms, all 48 weeks of triple therapy

– 1:1:1:1 ratio (n=12 each group)

Pol S, et al. EASL 2011, Berlin, P1373

PR

BMS-790052 3 mg QD/PR



48 weeks

Followup

24 weeks

SVR12


SVR12 with BMS-790052, an NS5A Inhibitor,

in Naive-G1 Patients

0

20

40

60

80

100

Placebo 3 mg 10 mg 60 mg

SVR12

RVR

eRVR

25

8 8

42

42

42 42

92 92

83

92 92 83 83 83

75


3 breakthroughs, 5 relapses with NS5A inhibitor

(2 of each in the 3 mg group)

%



Safety Data: BMS-790052 SVR Study

No hematology signal

No ALT signal

4 discontinuations for AEs in the 60 mg group vs 1 discontinuation in the 3 and 10 mg groups

– Appeared related to PR


Alisporivir (DEB025) Plus PR in G1

Treatment-naive Patients

Cyclophilin inhibitor – Inhibits cyclophilins, which augment viral replication

– Potent pangenotypic activity

– Expected to have a high barrier to resistance

N=288

Four arms:

-Alisporivir + PR 48 wks

-Alisporivir + PR 24 wks

-Alisporivir + PR RGT by RVR (24 vs 48 wks)

-PEG IFN + RBV

Alisporivir = 600 mg BID first week, then 600 mg QD

Flisiak R, et al. EASL 2011, Berlin, O4


Alisporivir (DEB025) plus PR in Genotype 1

Treatment-naive Patients (n=288)

0

20

40

60

80

100

Alisporivir

+ PR

48 wks

Alisporivir

+ PR

24 wks

Alisporivir

+ PR

RGT

PR

48 wks

SVR

(%)


76

53

69

55



0

20

40

60

80

100



RVR

(<25 IU/ml)

%

44

53

42

15


24* 28* 23* 8*

Alisporivir

+ PR

48 wks

Alisporivir

+ PR

24 wks

Alisporivir

+ PR

RGT

PR

48 wks

*HCV RNA neg


0

20

40

60

80

100

Relapse

%

15

39

16

24

Alisporivir

+ PR

48 wks

Alisporivir

+ PR

24 wks

Alisporivir

+ PR

RGT

PR

48 wks




Alisporivir (DEB025) plus PR in G1

Treatment-naive Patients

No null responses with DEB025 for 12 wks (n=196)

Viral breakthrough in 4.7% with DEB025 vs 5.5% for PR

–2.8% had full dose of DEB025 at breakthrough

Hyperbilirubinemia ↑ with DEB025 vs PR (33% vs 1%)

Bilirubin ≥5 x ULN in 4.2% with DEB025, reversible, no ALT elevations

Jaundice in ~10% of pts

Bilirubin elevation attributed to transporter effect



INFORM-1

The Study that Ushered in the Era

of Interferon-Free DAA Combinations


Gane EJ, et al. Lancet 2010;376:1467–75

INFORM-1: Danoprevir (Protease Inhibitor) +

Mericitabine (Nucleoside Polymerase Inhibitor)

Dose-ranging Phase I study of danoprevir (R7227/ITMN-191) plus mericitabine (R7128) for 14 days, followed by Peg-IFN/RBV up to Week 48, in HCV genotype-1 patients

Week 48 Day 14

Treatment-naïve

Mericitabine 500mg BID + Danoprevir 100mg Q8h

PR B n=8 active n=2 placebo

Mericitabine 500mg BID + Danoprevir 200mg Q8h

PR C1 n=8 active n=1 placebo

mericitabine 1,000mg BID + Danoprevir 100mg Q8h

PR C2 n=8 active n=1 placebo

Mericitabine 1,000mg BID + Danoprevir 200mg Q8h

PR D n=8 active n=4 placebo

Mericitabine 1,000mg BID + Danoprevir 900mg BID

PR G n=8 active n=2 placebo

Previous nonresponders (excluding null

responders)

Mericitabine 1,000mg BID + danoprevir 600mg BID

PR E n=8 active n=2 placebo

Previous null responders

Mericitabine 1,000mg BID + danoprevir 900mg BID

PR F n=8 active n=2 placebo



Nucleoside (RG7128) + Protease Inhibitor(RG7227)

G1 Interferon-Naive and Null Responders

Gane EJ, et al. Lancet 2010;376:1467-75

RG7128 1000 mg BID + RG7227 900 mg BID

INFORM-1: HCV RNA Undetectability in

Different Treatment Arms

Nulls Non-

responders

Treatment naïve patients

HCV

RNA

neg

(%)

Gane EJ, et al. Lancet 2010;376:1467–75

MCB 1000 mg bid

+ Danoprevir 900 mg bid


Effect of Host IL28B Genotype on Early Viral Kinetics

During IFN-free Treatment in Patients With CHC

INFORM-1 Cohorts C-G

0

1

2

3

4

5

CC Non-CC

Mean change in

HCV RNA after

13 days (log10 IU/ml)

5.01 4.59

n=12 n=33

0

20

40

60

80

100

CC Non-CC

50

27

Undetectable

HCV RNA at

day 14 (%)

n=12 n=33

Chu T, et al. EASL 2011, Berlin, P1323


Two Proofs of Concept in One Study: NS3 Protease Inhibitor and

NS5A Replication Complex Inhibitor


BMS-650032 (Protease Inhibitor)

+ BMS-790052 (NS5A Inhibitor + PR)

Phase IIa study of BMS-790052 plus BMS-650032, with or without Peg-IFN/RBV, for 24 weeks in HCV genotype-1 noncirrhotic null responders

Lok A, et al. J Hepatol 2011;54(Suppl. 1):S536

PR: peginterferon alfa-2a (180 µg/wk) + ribavirin (1000–1200 mg/day)

Cirrhotic patients excluded

BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID)

(n=11)

BMS-790052 + BMS-650032 +

PEG IFN + RBV (n=10)

24-week treatment

Dual

Quad


BMS-650032 (PI) + BMS-790052 (NS5A) + PR

n/N (%)

DUAL

BMS-790052 + BMS-650032

n=11

QUAD

BMS-790052 + BMS-650032 + PR

n=10

SVR24 4/11 (36)

(2/2 G1b, 2/9 G1a) 9/10 (90)*

Breakthrough 6/11 (55)

(all GT-1a) 0/10 (0)

Lok A, et al. J Hepatol 2011;54(Suppl. 1):S536

McPhee F, et al. J Hepatol 2011;54(Suppl. 1):S28

*The 10th patient had detectable HCV RNA at f/u week 24

but was subsequently undetectable



Quad therapy with BMS-790052, BMS-650032 and PR

gives 100% SVR24 in G1 null responders

Safety

– Dual: Diarrhea 73%, fatigue 55%,headache 46%

– Quad: Diarrhea 70%, fatigue 70%, headache 50%, nausea 50%

– LFTs: ALT elevations >3 x ULN in 6 pts (bilirubin<2x ULN)

-4 in dual group (2 on PR), 2 in quad group

1. Lok A, et al. EASL 2011, Berlin, O1356; 2. McPhee F, et al. EASL 2011, Berlin, P1223

Telaprevir (PI) + VX-222 (non-nuc): ZENITH

ZENITH: Phase II study of telaprevir (T) plus VX-222, with or without Peg-IFN/RBV,

for 12 weeks in treatment-naïve HCV genotype-1 patients

Week 12 12

Di Bisceglie AM, et al. J Hepatol 2011;54(Suppl. 1):S540

NS3/4A protease inhibitor plus NS5B non-nucleoside polymerase inhibitor


36

A n=18

DUAL

B n=29

VX-222 100mg BID + telaprevir 1125mg BID

VX-222 400mg BID + telaprevir 1125mg BID

Detectable at W2 or 8: PR up to W36

Undetectable W2 & 8: STOP treatment at W12

C n=29

D n=30

QUAD

VX-222 100mg BID + telaprevir 1125mg BID + PR

VX-222 400mg BID + telaprevir 1125mg BID + PR

Undetectable W2 & 8:

STOP treatment at W12

Detectable at W2 or 8:

PR up to W24

24


No virologic breakthrough in quad-therapy arms

Virologic breakthrough common in VX-222/TVR dual-therapy arms (17% to 31%)

Both dual regimens stopped early per protocol

HC

V R

NA

un

dete

cta

ble

(%

)

22 17

0 0

24

59

14

24

38

86

38

83

57

87

50

90

0

20

40

60

80

100

Week 2 Week 4 Weeks 2 & 8* Week 12

VX-222 100mg + telaprevir (n=18)

VX-222 400mg + telaprevir (n=29)

VX-222 100mg + telaprevir + PR (n=29)

VX-222 400mg + telaprevir + PR (n=30)

Telaprevir (PI) + VX-222 (non-nuc): ZENITH

*Indicates patients eligible to stop treatment at Week 12

Di Bisceglie AM, et al. J Hepatol 2011;54(Suppl. 1):S540

4 18

7 29

11 29

17 30

3 18

17 29

25 29

26 30

4 29

11 29

15 30

7 29

24 29

27 30


Ribavirin: The Drug That Won’t Go Away



GS-9256 (Protease Inhibitor) +

Tegobuvir (Non-nucleoside Polymerase Inhibitor)

Phase II study of tegobuvir plus GS-9256 for 4 weeks, with or without RBV or Peg-IFN/RBV, followed by PR up to Week 48, in treatment-naïve HCV genotype1 patients

48 Week

Part A

Part B PR

GS-9256 75mg BID + tegobuvir 40mg BID +

PR (n=15)

GS-9256 75mg BID + tegobuvir 40mg BID +

RBV* (n=15)

PR

GS-9256 75mg BID + tegobuvir 40mg BID*

(n=16) PR

4

Zeuzem S, et al. Hepatology 2010;52(Suppl.):400A

*Peg-IFN/RBV started early in the case of virologic breakthrough



Day

Med

ian

HC

V R

NA

(IU

/ml)

Lo

g 1

0

0

1

3

2

4

7 14 21 28

6

5

7

GS-9256: protease inhibitor

GS-9190: polymerase inhibitor

GS-9256 + GS-9190 (n = 15)

GS-9256 + GS-9190 + RBV (n = 13)

GS-9256 + GS-9190 + PEG IFN/RBV (n = 3)

Breakthrough = resistance

GS-9256 (Protease Inhibitor)+ GS-9190 (Non-nuc

Polymerase) Inhibitor + Ribavirin vs Quad

Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1.


BI 201335 (PI) + BI 207127 (non-nuc): SOUND-C1

SOUND-C1: Phase Ib study of BI 201335 plus BI 207127, in combination with

RBV, for 28 days in treatment-naïve HCV genotype-1 patients


24

120mg BI 201335 QD + PegIFN/RBV

400mg BI 207127 TID + 120mg BI 201335 QD +

RBV

Week

1 n=15

2 n=17

600mg BI 207127 TID + 120mg BI 201335 QD +

RBV

PR

4 48

PR

120mg BI 201335 QD + PegIFN/RBV

Cirrhotic patients excluded


BI 201335 (PI) + BI 207127 (non-nuc): SOUND-C1


6/15 14/17 17/17 10/15 11/15 17/17

40

6773

82

100 100

0

20

40

60

80

100

Day 15 Day 22 Day 29

Pa

tie

nts

with

HC

V R

NA

<2

5 I

U/m

L (

%)

400 mg TID BI 207127 + BI 201335 + RBV

600 mg TID BI 207127 + BI 201335 + RBV

6/15 14/17 17/17 10/15 11/15 17/17

Conclusions (1)

DAA classes other than protease inhibitors will play a critical role in the evolution of HCV therapy

Extent to which DAA class should be studied with PR depends on the class and the specific drug

Non-nucleosides unlikely to be competitive with other classes in combination with PR alone; more likely to play an adjunctive role

Quad regimens have major potential for benefit in null responders and other refractory populations

– Dilemma for clinicians, especially investigators

– Tolerability and dosage schedules will be important given complexity imposed by number of drugs



Conclusions (2)

Proof of concept for curability of HCV without IFN now exists

– Many believe SVR rates will be very high

– Even if not, large population of IFN-incapable patients would benefit

A dual DAA combination MUST contain one drug with high resistance barrier; otherwise, a third drug is needed

Unknown if 3-drug regimen requires a high resistance barrier component (but it couldn‘t hurt)

Ribavirin has potential to remain an important adjunct

Final aim for a DAA combination regimen (adapted from Dr S Zeuzem)

– All oral

– QD or BID

– Safe and well tolerable

– Limited drug-drug interactions

– Pan-genotypic

– IL28-independent

Documents

Non-Protease Novel Agents for Chronic Hepatitis C