Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,

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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09

HCV SPRINT-1HCV SPRINT-1

Final Results SVR 24Final Results SVR 24 Boceprevir* plus PegIFN Boceprevir* plus PegIFN -2b/Ribavirin -2b/Ribavirin

HCV 1 Treatment Naïve PatientsHCV 1 Treatment Naïve PatientsPaul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,

John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro,

Frank H Anderson, Ira M Jacobson, Raymond Rubin,Frank H Anderson, Ira M Jacobson, Raymond Rubin, Kenneth Koury, Lisa Pedicone, Eirum Chaudhri, and Janice K Albrecht Kenneth Koury, Lisa Pedicone, Eirum Chaudhri, and Janice K Albrecht

EASL April 23, 2009

Copenhagen, Denmark* NS3 Protease Inhibitor

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Aims of the Study

Evaluate safety/efficacy of Peg-IFN alfa-2b 1.5 µg/kg plus RBV in combination with boceprevir

Assess impact on SVR– RVR and EVR– Effect of the 4-week lead-in which allows

• Achievement of steady-state drug levels• Alpha interferon-mediated immune system activation• Lower HCV burden• Potentially decreased pool of pre-existing viral quasi-species

– 28 vs. 48 week treatment duration– Decreased ribavirin from 800-1400 mg/d to 400-1000 mg/d

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SPRINT-1 Study DesignWeek 4 Week 28 Week 48

Lead-inStrategy

Control

No Lead-inStrategy

Low DoseRBV Strategy

N=104

N=59

N=16

aPart two consisted of 75 patients in 10 US sites, 1:4 randomization.

N=103

N=107

N=103

N=103

Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 48 wks


Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg for 48 wks



24 wksFollow-up

24 wksFollow-up

24 wksFollow-up

44 wks Follow-up

24 wksFollow-up

Peg-IFN2b + RBV

800-1400 mg 44 wks

Follow-upPeg-IFN2b 1.5 μg/kg +

RBV 800-1400mg + Boceprevir 800 mg TID for 24 wks


Peg-IFN2b + RBV

800-1400 mg 24 wks

Follow-up

PAR

T 1

PAR

T 2a

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Baseline Characteristics

a Boceprevir added to treatment regimen after 4 week lead-in of Peg-IFN alpha-2b + RBV.

P/RControl 48 wksN=104

P/R/B28 wksN=107

P/R 4 wks P/R/B 24 wksN=103a

P/R/B48 wksN=103

P/R 4 wks P/R/B 44 wksN=103a

P/R/B48 wksN=16

P/low dose R/B

48 wksN=59

GenderMale (%) 67 59 50 61 56 56 69

RaceCaucasian (%) 80 80 83 84 83 75 73Black (%) 15 17 15 14 15 25 27

Mean age (years) 48.3 46.4 47.7 46.7 47.6 50.3 48.7Mean weight (kg) 83.4 83.4 79.9 80.0 78.4 81.4 88.5HCV subtype (%)

1a 51 63 51 53 58 44 661b 40 28 36 35 34 44 31

1 (no sub-type) 9 9 13 12 8 13 3

Viral load mean (log10 IU/mL) 6.53 6.64 6.53 6.54 6.53 6.43 6.47

HCV-RNA >600,000 IU/mL (%) 90 92 87 91 90 81 83

Cirrhosis (%) 8 7 7 9 6 0 7

PART 1 PART 2

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Sustained Virologic Responsea

aRoche COBAS TaqMan LLD <15 IU/mL; bP = 0.013; cP = 0.005; dP <0.0001; eP <0.0001 compared to P/R Control; f1 late relapser after follow-up week 24, not included n SVR.

Part 2

0

10

20

30

40

50

60

70

80

P/R/B 48 wks

50

P/low dose R/B 48 wks

36

N=16 N=59

Part 1

% P

atie

nts

HC

V N

egat

ive

% P

atie

nts

HC

V N

egat

ive

0

10

20

30

40

50

60

70

80

38

54b 56c

67d

P/R Control 48 wks

P/R/B 28 wksf

P/R 4 wks P/R/B

24 wks

P/R/B 48 wks

P/R 4 wks P/R/B

44 wks

75e

N=104 N=107N=103

N=103N=103

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Predictability of SVR: RVR and EVR

aRoche COBAS TaqMan LLD <15 IU/mL; bRVR: undetectable HCV-RNA on or before 4 wks of boceprevir treatment; undetectable HCV-RNA on or on before 4 weeks for P/R control cEVR: undetectable HCV-RNA on or before 12 wks of boceprevir treatment; undetectable HCV-RNA on or before 12 weeks for P/R control

All Patients Patients with RVRb Patients with EVRc

SVRa by time to first PCR-negative HCV RNA

0

20

40

60

80

100

120

% o

f Pat

ient

s H

CV

Neg

ativ

e

P/R Control 48 wks

38

56

75

100

8294

86

68

91P = 0.005

P <0.0001

N= 104 103 103 8 66 66 37 85 85

P/R 4 wks P/R/B 24 wks P/R 4 wks P/R/B 44 wks

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Predictability of SVR: RVR and EVRSustained Virologic Responsea % (n/N)

Treatment Arm All Patients Patients with RVRb Patients with EVRc

P/R Control 48 wks 38(39/104)

100 (8/8)

86(32/37)

P/R/B 28 wks 54d

(58/107)74

(32/43)68

(58/85)P/R 4 wks P/R/B 24 wks

56e

(58/103)82

(54/66)68

(58/85)

P/R/B 48 wks 67f

(69/103)84

(32/38)84

(68/81)P/R 4 wks P/R/B 44 wks

75g

(77/103)94

(62/66)91

(77/85)

P/R/B 48 wks 50(8/16)

86(6/7)

73(8/11)

P/low dose R/B 48 wks 36(21/59)

75(12/16)

60(21/35)

aRoche COBAS TaqMan LLD <15 IU/mL; bRVR: undetectable HCV-RNA on or before 4 wks of boceprevir treatment; undetectable HCV-RNA on or on before 4 weeks for P/R control cEVR: undetectable HCV-RNA on or before 12 wks of boceprevir treatment; undetectable HCV-RNA on or before 12 weeks for P/R control; dP = 0.013; eP = 0.005; fP <0.0001; gP <0.0001 compared to P/R control

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Effect of Treatment Duration on SVR

aTime after Peg-IFN alpha-2b +RBV in control; time after boceprevir dosing in treatment arms.

Time to first PCR-negative HCV-RNAa

P/R Control48 wks% (n/N)

P/R 4 wks P/R/B

24 wks% (n/N)

P/R 4 wks P/R/B

44 wks% (n/N)

≤4 wks 100(8/8)

82(54/66)

94(62/66)

>4 wks – ≤12 wks 83(24/29)

21(4/19)

79(15/19)

>12 wks 30(7/23)

0(0/1)

0(0/1)

Never negative 0(0/44)

0(0/17)

0(0/17)

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Predictability of SVR Based onResponse During 4 Week P/R Lead-in

Log10 viral load decrease after 4 wks of P/R lead-in

SVRa

P/R 4 wks P/R/B24 wks%(n/N)

P/R 4 wks P/R/B44 wks%(n/N)

<0.5 29 (2/7) 44 (4/9)

0.5 < 1.0 24 (5/21) 62 (8/13)

1.0 < 1.5 30 (3/10) 65 (11/17)

1.5 < 2.0 73 (8/11) 80 (8/10)

2.0 < 3.0 67 (14/21) 79 (11/14)

3.0 < 4.0 83 (10/12) 82 (14/17)

≥4.0 100 (11/11) 92 (11/12)

Undetectable 100 (3/3) 100 (9/9)aUndetectable HCV-RNA using Roche COBAS TaqMan with LLD <15 IU/mL; 7 and 2 patients were missing week 4 virology in 28 and 48 wk groups, respectively.

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SVR Rates and AnemiaAnemia (Hgb <10 g/dL)No Anemia (Hgb ≥10 g/dL)

0

10

20

30

40

50

60

70

80

90

100

48

35

67

47

88

6458

30

P/R Control48 wksa

P/R 4 wks P/R/B 24 wksa

P/R 4 wks P/R/B 44 wks

P/low dose R/B48 wks

aOne patient in each group missing in-treatment hemoglobin values

n/N=

% o

f Pat

ient

s H

CV

Neg

ativ

e

12/25 27/78 34/51 24/51 42/48 35/55 7/12 14/47

Epo Use n/N= 19/25 8/78 41/51 9/51 43/48 10/55 9/12 0/47

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45 46

10

0 0

23

50

27

0 0

25

46

27

20

4946

5

0 00

10

20

30

40

50

60

Hemoglobin: Nadir WHO Grade Category Observed During Treatment Period

% o

f Pat

ient

s

Grade 0(≥11 g/dL)

Grade 1(9.5 – <11.0 g/dL)

Grade 2 (8.0 – <9.5 g/dL)

Grade 3 (6.5 – <8.0 g/dL)

Boceprevir added to treatment regimen after week 4 lead-in of Peg-IFN alpha-2b + RBV.

P/R Control 48 wksP/R 4 wks P/R/B 24 wksP/R 4 wks P/R/B 44 wksP/low dose R/B 48 wks

Grade 4 (6.5 – <g/dL)

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Overall Relapse and Relationship to RVROverall Relapse and Relationship to RVR

aP = 0.0079; bP = 0.0002 compared to P/R Control.

P/R Control 48 wks

P/R/B 28 wks

P/R 4 wks

P/R/B 24 wks

P/R/B 48 wks

P/R 4 wks

P/R/B 44 wks

% R

elap

se%

Rel

apse

P/R/B

48 wks

P/low dose R/B 48 wks

Part 2

11

22

00

5

10

15

20

25

30

35

Part 1

24

30

24

7a

3b

00

5

10

15

20

25

30

35

Relapse overall

14

21

11

6

2

Relapse in RVR pts

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Most Common Adverse Events*

aBased upon counts for all treatment groups combined, >30%

P/R Control 48 wks N=104

P/R/B28 wks N=107

P/R 4 wks P/R/B

24 wks N=103

P/R/B48 wks N=103

P/R 4 wks P/R/B

44 wks N=103

P/R/B48 wks N=16

P/low dose R/B

48 wksN=59

Fatigue 55 61 68 50 71 69 68

Anemia 34 56 53 52 56 63 24

Headache 43 49 40 43 52 81 49

Nausea 43 38 41 54 47 63 59

Insomnia 38 34 28 39 40 44 39

Pyrexia 34 26 26 40 34 44 44

Chills 34 29 30 32 34 31 44

Alopecia 26 34 29 29 34 31 32

Diarrhea 22 26 26 24 28 31 24

Dysgeusia 9 21 26 32 27 44 31

Neutropenia 12 23 17 25 30 19 32

Influenza like illness 24 22 20 18 15 38 19

Arthralgia 20 13 21 20 18 31 19

Dizziness 15 18 16 20 14 44 19

Vomiting 5 22 15 24 17 44 19

Decreased Appetite 12 7 14 17 12 38 27

Injection Site Reaction 10 8 5 9 11 25 36

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Treatment Discontinuations (%)

P/R Control 48 wks

% (N=104)

P/R 4 wks P/R/B24 wks

% (N=103)c,d

P/R 4 wks P/R/B44 wks

% (N=103)c

P/low dose R/B48 wks

% (N=59)

EPOn = 27

No EPOn = 77

EPOn = 50

No EPOn = 53

EPOn = 53

No EPOn = 50

EPOn = 9

No EPOn = 50

Total 7 18 14 38 15 38 11 60

Adverse Events 4 9 2 26 8 10 0 14

Viral Breakthrougha 0 0 6 2 4 6 11 30

Otherb 4 9 6 9 4 22 0 16

aPersistent ≥2 log10 increase from nadir and ≥50,000 IU/mL; bLost to follow-up, subject did not wish to continue, non-compliance with protocol; cBoceprevir added to treatment regimen after 4 wk lead-in of Peg-IFN alpha-2b + RBV; d6 patients discontinued during lead-in period prior to Boceprevir

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Mutations Observed by Population Sequencing in SPRINT-1 Trial

Major(≥25%)

Less Common(≥5% to <25%)

Infrequent(<5%)

V36M V36A, V36L

T54S T54A

V55A

R155K R155T

A156S

V158I

V170A I170T

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Summary Boceprevir significantly improves SVR

– Boceprevir with SOC for 48 weeks nearly doubles SVR– Week 4 P/R response, RVR, and EVR all show promise for response

guided therapy – Anemia appears to be a surrogate for response– Full dose RBV required

Safety– Boceprevir is well-tolerated for up to 48 weeks– No boceprevir-defining toxicity responsible for treatment

discontinuation– Boceprevir is associated with ~1 g/dL incremental hemoglobin

decrease– Anemia management with EPO is associated with increased

completion rates

Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,

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