AASLD 2010 HCV FeedbackOctober 29 - November 2, 2010

Boston, Massachusetts

Dr Allister J GrantConsultant Hepatologist

Leicester Liver Unit

1. Boceprevir, a potent inhibitor of HCV NS3 protease

2. Telaprevir, a potent inhibitor of HCV NS3/4A protease

3. Both being tested in combination with standard-of-care peginterferon alfa-2/ ribavirin in phase III studies in chronic HCV infection

Trials reported at AASLD 2010

1. Boceprevir

• SPRINT-2: naive GT1 patients

• RESPOND-2: nonresponder GT1 patients

2. Telaprevir

• ADVANCE: naive GT1 patients

• ILLUMINATE: response-guided therapy in naive GT1 patients

Boceprevir and Telaprevir

Treatment-naive patients with

genotype 1 HCV(2 cohorts:

N = 938 nonblack and 159

black)

PR*(n = 316,

52)

PR*(n = 311 nonblack, 52 black)

Wk 72Wk 48

Follow-up

Follow-up

Wk 28

Follow-up

Wk 4

BOC + PR*(n = 316 nonblack,

52 black)

BOC + PR*(n = 311 nonblack, 55 black)

PR*(n = 311,

55)

PR*

*BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. †Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays.

Poordad F, et al. AASLD 2010. Abstract LB-4.

Follow-upRVR†

No

RVR

Phase III, Randomized, placebo-controlled trial

SPRINT-2: Boceprevir + PegIFN/RBV in G1 Tx-Naive Patients

PR*(n = 311,

52 )

0

20

40

60

80

100

Pat

ient

s (%

)

SVR Relapse

4-wk PR + 44 weeks BOC + PR4-wk PR + response-guided BOC + PR 48-wk PR

67 68

40

8

23

9

0

20

40

60

80

100

Pat

ient

s (%

)

SVR Relapse

4253

2317 1412

Nonblack Patients Black Patients

P < .0001P = .044

P = .004

Poordad F, et al. AASLD 2010. Abstract LB-4.

n = 211 213 125 21 18 37 22 29 12 3 6 2

SPRINT-2: Response Rates According to Race

SPRINT-2: Response Rates

• >1 log drop in VL at wk 4:– 82% SVR for both B/PR arms

• <1log drop in VL at wk 4:– 28% SVR in RGT (response guided therapy)– 38% SVR in 44BOC/PR

• PCR neg at week 4 and 8– 97% SVR in RGT (47% of patients)– 98% SVR in 44BOC/PR

RESPOND-2:Boceprevir in G1 Prior Non-responders to PegIFN/RBV

Phase III, Randomised

PR*(n = 80)

PR*(n = 161) BOC + PR*

BOC + PR* PR*(n = 162)

BOC + PR*If detectable

at Wk 8 PR*

Bacon BR, et al. AASLD 2010. Abstract ♯216.

Treatment-experienced patients with

GT1 HCV(N = 403)

Wk 48Wk 8 Wk 36

Follow-up†

Follow-up†

Follow-up†

Follow-up†

*BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day.†Follow-up for 24 wks after completion of therapy.

Wk 4

0

20

40

60

80

100

Overall

SV

R (%

)

4-wk PR + 44-wk BOC + PR (n = 161)

59*

PreviousNonresponders

PreviousRelapsers

48-wk PR (n = 80)

4-wk PR + response-guided BOC + PR (n = 162)

66

21

40

52

7

75

29

69

P < .0001 vs control

(both arms)

Bacon BR, et al. AASLD 2010. Abstract 216.

95/162

107/161

17/80

23/57

30/58 2/29

72/105

77/103

15/51

RESPOND-2: SVR Rates According to Treatment Arm and Prior Response

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

Treatment-naive patients infected with genotype 1

HCV

(N = 250)

12-Wk Arm TVR* + PegIFN/RBV†

(n = 17)

PegIFN/RBV*

PegIFN/RBV*

Wk 12

48-Wk Control ArmPegIFN/RBV† + Placebo

(n = 75)

24-Wk ArmTVR* + PegIFN/RBV†

(n = 79)

48-Wk Arm TVR* + PegIFN/RBV†

(n = 79)

PegIFN/RBV*

Wk 24 Wk 48

24-wk follow-up

24-wk follow-up

24-wk follow-up

24-wk follow-up

*1250 mg loading dose of TVR administered on Day 1, then 750 mg 3 times daily.†PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.

PROVE 1: Combination of Telaprevir with PegIFN/Ribavirin significantly increases SVR in treatment-naïve patients with HCV Genotype 1

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

0

20

40

60

80

100

Patie

nts (

%)

12-wk TVR + 48-wk pegIFN/RBV (n = 79)12-wk TVR + 24-wk pegIFN/RBV (n = 79)12-wk TVR + pegIFN/RBV (n = 17)

Control (n = 75)

SVR Relapse

35

61†

41

67‡

33

2

23

6

N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.

PROVE 1: Results

Frequency of undetectable HCV RNA levels during and after treatment

Week T12/PR24N=79

T12/PR48N=79

T12/PR12N=17

PR48N=75

4 64(81%) 64(81%) 10(59%) 8(11%)

12 54(68%) 63(80%) 12(71%) 34(45%)

24 45(57%) 56(71%) NA 43(57%)

48 NA 51(65%) NA 35(47%)

SVR 48(61%) 53(67%) 6(35%) 31(41%)

12% 14%

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

T12/PR24 vs T12/PR48

T12/PR24 T12/PR48RVR 81% 81%SVR 61% 67%

Relapse 2% 6%DC 2° to A/E 25.3% 13.9%

Dropouts 47% 32%

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

PROVE 1: Conclusions

1. Coadministration of a 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV significantly increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone

2. Coadministration of TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV

3. TVR coadministration increased rate of treatment discontinuation due to adverse effects, predominantly rash

McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

Prove 3

McHutchison JG, et al. AASLD 2009. Abstract 66, NEJM 2010.

Outcome Control Arm

(n = 114)

12-Wk TVR +24-Wk

PegIFN/RBV (n = 115)

24-Wk TVR + 48-Wk

PegIFN/RBV(n = 113)

24-Wk TVR +PegIFN

(n = 111)

SVR, % 14 51* 53* 24†

Previous nonresponders, % (n/N) 9 (6/68) 39* (26/66) 38* (24/64) 11‡ (7/62)

Previous relapsers, % (n/N) 20 (8/41) 69* (29/42) 76* (31/41) 42§ (16/38)

Cirrhotics % 8 53 45 18

*P < .001 vs control. †P = .024 vs control. ‡P = .297 vs control. §P = .029 vs control.

24 vs 48wks of T/PR in patients with G1 previously treated with PEG IFN/ RBV-

Week 4 non-response - <1log decline in control arm or detectable HCV in TPR arms

ADVANCE: Telaprevir + PegIFN/RBV in G1 Tx-Naive Patients

Wk 12

TVR + PR*(n = 364)

TVR + PR*(n = 363)

PR*(n = 361)

eRVR†: PR*

Wk 72Wk 48Wk 8

Follow-up

Follow-up

Follow-up

*TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.

Jacobson IM, et al. AASLD 2010. Abstract 211.

Wk 24

PR*

eRVR†: PR*

PR*

Follow-up

Follow-up

Phase III, Randomized, placebo-controlled trial

Treatment-naive patients with

genotype1 HCV(N = 1088)

ADVANCE:1088 Treatment naïve G1 patients randomised:

TPV/PEG/RBV x8 weeks then PEG /RBV x16 weeks (T8/PR24)TPV/PEG/RBV x12 weeks then PEG /RBV x12 weeks (T12/PR24)PEG/RBV x48 weeks (PR48)

RESULTS:T8/PR24N=364

T12/PR24N=363

PR48N=361

RVR (%) 67 68 9

eRVR (%) 57 58 8

SVR (%) 69 75 44

eRVR-SVR 83 89 97

Completion % 71.4 73.8 56

PR Viral breakthrough

10.2 5 NA

Jacobson I AASLD ♯211Kiefer T AASLD LB-11

ILLUMINATE:Response-Guided Telaprevir + PegIFN/RBV in G1 Naive Pts

Treatment-naive patients

with GT1 HCV(N = 540)

PR*(n = 162)

PR*(n = 160)

Wk 72Wk 48Wk 24

Follow-up

Follow-up

*TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.

Sherman KE, et al. AASLD 2010. Abstract LB-2.

Follow-up

Phase III Open-label, randomized trial, ITT analysis

Wk 20

eRVR†

No eRVR†

PR*(n = 218)

TVR + PR*

Wk 12

PR*

0

20

40

60

80

100

24-wk therapy

SV

R (%

)

92

48-wk therapy

88

Overall

72

Patients With eRVR

n/N = 388/540 149/162 140/160

Sherman KE, et al. AASLD 2010. Abstract LB-2.

ILLUMINATE: Overall SVR Rates

ILLUMINATE:

• Adverse Events– Anaemia <8.5

• 9% in TPV• 2% in PR• 0.6% DC

– Fatigue (1.1% DC)– Rash

• Eczematous rash in 37%• 7% severe rash

– Pruritis – Nausea

• Overall discontinuation rate 17%

• In first 12 weeks there was:– 7% DC of all drugs– 12% DC of Telaprevir

Interferon Free Therapy?BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in G1 Null Responders

Lok A, et al. AASLD 2010. Abstract LB-8.

Prior null responders

with GT1 HCV(N = 21)

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

(n = 11)

Wk 72Wk 24

Follow-up

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

+ PR*(n = 10)

Open-label, randomized, placebo-controlled phase IIa trial

BMS-790052: NS5A polymerase inhibitor

BMS-650032: NS3 protease inhibitor

Follow-up

*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.

Wk 12 Interim Analysis

64

3646

60 60

90

0

20

40

60

80

100

RVR eRVR cEVR

BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR

Patie

nts (

%)

7/11 6/10 6/104/11 5/11 9/10

All viral breakthroughs occurred in patients with GT1a

Lok A, et al. AASLD 2010. Abstract LB-8.

Other Protease/Polymerase Inhibitors• TMC435- NS3/4a Protease inhibitor (PILLAR Trial)

– Phase IIa , G1 Naive– Once Daily– 12-24 weeks Rx +PR48– SVR 91%-98% (4 vs12 wks )

• Daneprovir– RG7227 phase II, in G1 naive patients (ATLAS trial) – 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs 43% with SOC

• Vaniprevir- NS3/4a Protease Inhibitor– MK-7009 phase IIa study G1 naive patients without cirrhosis– Significantly higher when combined with pegIFN/RBV vs SOC

• RVR: 67% to 84% vs 5%

Fried M, et al. AASLD 2010. Abstract LB-5.

Terrault N, et al. AASLD 2010. Abstract 32.

Manns MP, et al. AASLD 2010. Abstract 82

HCV Pharmacogenetics• GWAS used patients from IDEAL and Muir Studies• 1137 samples on patients with SVR• SNP’s

rs12979860 on Chr 19 strongly associated with SVR & localised to IL28β

SV

R %

Thomas DL, et al. Nature. 2009;461:798-801.

Thomas DL, et al. Nature. 2009;461:798-801.

Regional Distribution of IL28B rs12979860 CC Genotype

IL28β polymorphisms associated with– Higher SVR rates[1]

– Higher RVR rates[2]

– Higher HCV RNA[3]

– Higher LDL levels[4]

– Higher baseline ALT levels[5]

– Higher rate of spontaneous viral clearance[6]

1. Ge D, et al. Nature. 2009;461:399-401. 2. Mangia A, et al. AASLD 2010. Abstract 897. 3. Liu L, et al. AASLD 2010. Abstract 231. 4. Saito H, et al. AASLD 2010. Abstract 732. 5. Thompson AJ, et al. AASLD 2010. Abstract 1893. 6. Thomas DL, et al. Nature. 2009;461:798-801.

IL28β Associations in Patients With Hepatitis C

And if time

♯214:Maintenance PEG IFN to prevent HCC

• Extended FU from HALT-C trial• 1084 patients 6.1-8.7yr FU• 88 HCC (20 clinical HCC)• No difference between Rx and Control at 3/5/7yr

• Subgroup analysis– Cirrhotics who had PEG for >2 years-

marginal benefit

A Lok et al AASLD 2010, Abstract 214

EXTEND Trial:Long Term FU of PROVE 1-3 patients

• 3 yr FU of T/PR treated patients• 123 patients who had SVR’s from previous

studies• 122/123 had durable SVR (99%)• 79 patients without SVR analysed for

resistance and after 22 mo 89% reverted to wild type

S Zeuzem et al AASLD 2010 , Abstract 227

♯213: Effect of SVR on all cause mortality

• Dept of Veterans Affairs Data Registry• 23000 patients• 16800 with post Rx RNA , SVR rate 44%

– 52% smokers, 20% DM, 15% COPD, 12% CAD, 26% alcohol, 36% depression– 1535 died (median 3.7yrs)

Time

Mortality

G1,2,3 with SVR

G1,2 No SVR

G3 No SVR