Triple Therapy Today: Phase III Results in G1 Relapsers and

Nonresponders

Bruce R. Bacon, M.D.James F. King MD Endowed Chair in Gastroenterology

Professor of Internal MedicineDivision of Gastroenterology and Hepatology

Saint Louis University School of MedicineSaint Louis University Liver Center

St. Louis, Missouri

Before May 2011

Approach to Pegylated Interferon/Ribavirin Nonresponders

• Retreat with other pegylated interferon• Retreat with Infergen• Refer for clinical trial • Watch and wait

After May 2011

• Approval of telaprevir and boceprevir• Added to PEG-Interferon/ribavirin• In naïve patients – SVR rates up to 75%• In partial responders and relapsers SVR rates

up to 60% to 85%

RESPOND-2 Previous Treatment Failure Patients Study Design (N=403)

Stopping Rule

Weeks 12 24 48 72

Placebo + PR44 wks

PR4 wks

Follow-up24 wks

Arm 1PR48

Control

TW 8 Undetectable

BOC + PR32 wks

PR4 wks

Follow-up36 wks

Placebo + PR12 wks

Follow-up24 wks

TW 8 Detectable

Arm 2BOCRGT

BOC + PR44 wks

PR4 wks

Follow-up24 wks

Arm 3BOC/PR48

8 36

Decision point for long vs. short therapy

Lead-in

Stopping Rule: Patients with detectable HCV-RNA at week 12 were discontinued from treatment for futility. Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight-based dosing of 600-1400 mg/day in a divided daily dose. BOC administered 800 mg TID.

21

5966

32

15 12

0

20

40

60

80

100

825

95162

RESPOND-2 SVR and Relapse RatesIntention to treat population

p < 0.0001

p <0.0001

SVR

Relapse Rate

1780

107161

17111

14121

12-week HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where missing data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/80), 58% (94/162) and 66% (106/161), respectively.

SVR rates in BOC RGT and BOC/PR48 arm not statistically different (OR, 1.4; 95% CI [0.9, 2.2])

% o

f Pa

tien

ts

PR 48 BOC RGT BOC/PR48

SVR by Week 8 HCV RNA Response Intention to Treat Population

100

86 88

12

40 43

0

20

40

60

80

100

Undetectable HCV RNA at Week 8

Detectable HCV RNA at Week 8

SV

R (

%)

6474

3070

7484

2972

46% of patients in BOC RGT arm were eligible for

shorter therapy

~6 times as many patients on BOC regimens (46-52%) achieved undetectable HCV RNA at week 8 compared to control (9%)

PR 48 BOC BOC/PR48 RGT

77

865

RESPOND-2: SVR in Prior Relapsers and Prior Non-Responders

1 20

20

40

60

80

100

29

7

69

40

75

52

SV

R (

%)

72105

1551

77103

2757

3058

Prior Relapsers Prior Partial Responders

BOC RGT

BOC/PR48

PR48 BOC RGT

BOC/PR48

PR48

HCV G1 patients with previous treatment failure

n/N= 229

Bacon B, et al. N Engl J Med. 2011;364(13):1207-1217. © 2011 Massachusetts Medical Society.

PR 4 Week Lead-In As a Predictor of Response

• Interferon responsiveness may not remain constant over time

• Viral load decline of <1 log10 after 4 weeks of PR is significantly correlated to a <2 log10 decline after 12 weeks of treatment1

– Phase 3 trial (IDEAL) of PR alone - only 4% (31/750) of patients with <1 log10 decline after 4 weeks of PR achieved SVR2

• Lead-in allows real time assessment of patient’s interferon responsiveness vs. historic response

• 26% (102/393) of RESPOND-2 patients had a < 1 log10 decline in HCV viral load at week 4

1. Poordad F, et al. AASLD, Boston, MA, 2010, abstract # 797

2. McHutchison JG, et al. NEJM. 2009; 360:1827-1838

25

7379

0

20

40

60

80

100

SVR by Week 4 PR Lead-In Response

Poorly Responsive to IFN<1 log10 viral load decline at

treatment week 4

Responsive to IFN≥1 log10 viral load decline at

treatment week 4

0

33 34

0

20

40

60

80

100

012

1546

1544

1767

80110

90114

SV

R (

%)

PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48

Triple Therapy with Boceprevir: Nearly Half of Previous Treatment Failures in the Boceprevir and PR Arms

Were Early Responders

Boceprevir RGT Boceprevir PR48 PR48

Boceprevir RGT Boceprevir PR48 PR48

Triple Therapy with Boceprevir: Patients Who Were Not Early Responders Still Achieved Virologic Cure (SVR)

Treatment Algorithm – Previous Treatment Failures Without Cirrhosis

Boceprivir+ PR for 32 weeks

Boceprivir + PR for 32 weeks

Treatment Algorithm – Patients With Compensated Cirrhosis, Historical Null Responders, and Poorly

Interferon Responsive Patients

Boceprevir +PR for 44 weeks

• Patients with compensated cirrhosis and historical null responders (patients with <2-log10 decline in HCV RNA by treatment week 12 of their previous therapy) should receive 4 weeks PR followed by 44 weeks boceprevir + PR

• Consideration should be given to treating treatment-naïve patients who are poorly interferon responsive (with <1 log10 decline in HCV RNA at treatment week 4) with 4 weeks PR followed by 44 weeks of boceprevir +PR

Safety Profile Over Entire Course of Therapy48 PRN = 80

BOC RGTN = 162

BOC/PR48N = 161

Median treatment duration, days 104 252 336

Deaths N=0 N=1 N=0

Serious AEs 5% 10% 14%

Discontinued due to AE 3% 8% 12%

Dose modification due to AE 14% 29% 33%

Hematologic parameters

Neutrophil count (<750 to 500/mm3 / <500/mm3)

9% / 4% 19% / 6% 20% / 7%

Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL) Discontinuation due to anemia Dose reductions due to anemia Erythropoietin use Mean (median) days of use

24% / 1%0%8%

21%65 (55)

43% / 5%0%

19%41%

135 (155)

35% / 14%3%

22%46%

130 (90)

Boceprevir Resistance Assoc Variants % (n/n) < 1 log10 Decline Wk 4 Lead-In

≥ 1 log10 Decline Wk 4 Lead-InNA 28% (13/46)

8% (9/110)32% (14/44)6% (7/112)

Boceprevir: Anemia Summary

• In clinical trials, patients treated with BOC had:– Average additional decrease of Hgb of approximately 1 g/dL– Higher frequency of Hgb reductions to Grade 3 or higher

• Mechanism of anemia thought to be result of bone marrow suppressive effect, not due to RBC hemolysis as was observed with RBV

• Anemia was managed with RBV dose reduction and/or erythropoietin– RBV dose reduction does not appear to impact BOC efficacy

• SVR rates with BOC higher in anemic vs non-anemic patients

US Food and Drug Administration; April 27, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252341.pdf. Accessed April 28, 2011. Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.

Boceprevir: SVR According to EPO Use and RBV Dose Reduction

N = 1097 treatment-naïve; N = 403 previous-treatment-failure

Retrospective analysis of SPRINT-2 and RESPOND-2

Sulkowski MS, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster 1800.

Previously Untreated (SPRINT-2)BOC arms only

Previous Treatment-Failures(RESPOND-2)

BOC arms only100

80

60

40

20

0

SV

R (

%)

Noanemia

EPOalone

NeitherBothR dosereduction

alone

Anemia

58

74 7871 68

212363

95129

2937

109153

3044

100

80

60

40

20

0

SV

R (

%)

Noanemia

EPOalone

NeitherBothR dosereduction

alone

Anemia

50

80 8372 73

83165

4759

56

4867

1926

Predictors of Sustained Virologic Response Among Poor Interferon

Responders When Boceprevir is Added to Peginterferon alfa-2b/Ribavirin

B. Bacon1, S. Bruno2, E. Schiff 3, P. Kwo4, M. Buti5, L. Pedicone6, W. Deng6, M. Burroughs6, C. Brass6, J. Albrecht6, S. Flamm7

1Saint Louis University School of Medicine, St. Louis, MO, 2A.O. Fatebenefratelli e Oftalmico, Milan, Italy, 3University of Miami, Miami, FL, 4Indiana University

School of Medicine, Indianapolis, IN, 5Vall d'Hebron University Hospital, Barcelona, Spain, 6Merck, Sharp & Dohme Corp., Whitehouse Station, NJ,

2Northwestern Feinberg School of Medicine, Chicago, IL

Background

Pre-treatment predictors of SVR for IFN-based therapies include IL-28B, baseline VL, virus genotype, age, ethnicity, body weight and fibrosis stage

In two phase 3 studies of BOC + PR, response to a 4 week PR lead-in was the strongest predictor of SVR– Poor IFN response (<1 log decline after lead-in)

occurred in up to 28% of patients in SPRINT-21 and RESPOND-22

– Among patients receiving BOC, 28-38% of the poor IFN responders achieved SVR, compared with 0-4% of poor IFN responders in the PR control arm

BOC, boceprevir; IFN, interferon; PR, peginterferon alfa-2b plus ribavirin; SVR, sustained virologic response; VL, viral load. 1. Poordad F, et al. N Engl J Med. 2011;364:1195-206.2. Bacon BR, et al. N Engl J Med. 2011;364:1207-17.

Objective

• To identify predictors of SVR in poor IFN responders (<1 log decline after 4 week PR lead-in) in patients with genotype 1 hepatitis C virus receiving BOC + PR

BOC, boceprevir; IFN, interferon; SVR, sustained virologic response.

HCV G1 Subtype as a Predictor of SVR inPatients with Poor IFN Response (BOC Arms

Combined)

20

54

27

43

25

47

0

20

40

60

80

100

% S

VR

1154

1935

33124

44178

2661

4596

1a 1b 1a 1b 1a 1b

RESPOND-2 SPRINT-2 CombinedStudies

p = 0.001 p = 0.028 p < 0.001

Baseline Fibrosis Score* as a Predictor of SVR inPatients with Poor IFN Response (BOC Arms

Combined)

41

21

37

15

38

17

0

20

40

60

80

100%

SV

R

2663

419

58157

84220

427

846

F0/1/2 F3/4

RESPOND-2 SPRINT-2 CombinedStudies

p = 0.029 p = 0.025 p = 0.007

F0/1/2 F3/4 F0/1/2 F3/4

*Excludes 1 patient with missing data for METAVIR score

Baseline Viral Load as a Predictor of SVR inPatients with Poor IFN Response (BOC Arms

Combined)

59

27

52

26

54

26

0

20

40

60

80

100

% S

VR

1017

2073

2752

3769

36140

56213

RESPOND-2 SPRINT-2 CombinedStudies

p = 0.014 p <0.001 P<0.001

≤ 2,000,000 IU/m

L

> 2,000,000 IU/m

L

≤ 2,000,000 IU/m

L

> 2,000,000 IU/m

L

≤ 2,000,000 IU/m

L

> 2,000,000 IU/m

L

SVR in Poor IFN Responders Based on Hemoglobin Decline (g/dL) During 4 Week PR

Lead-In (BOC Arms Combined)

3529

33 31 33 31

0

20

40

60

80

100

% S

VR

2266

828

39118

61184

2270

3098

RESPOND-2 SPRINT-2 CombinedStudies

≤ 3 > 3 ≤ 3 > 3 ≤ 3 > 3

SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL

VL) (BOC Arms Combined)

0

38

21

50

91

0

9

33

48

79

0

16

30

49

83

0

20

40

60

80

100

% S

VR

RESPOND-2 SPRINT-2 CombinedStudies

<3 3-4 4-5 >5

Undetectable

016

38

628

1020

1011

028

223

2370

1531

2329

<3 3-4 4-5 >5

Undetectable <3 3-4 4-5 >5

Undetectable

044

531

2998

2551

3340

Summary of Predictors of SVR in Poor IFN Responders

TW8 virological response– No patient with <3 log decline at TW8 achieved SVR– Patients with undetectable HCV RNA at TW8 had best

chance to achieve SVR

Pre-treatment factors predictive of SVR– Genotype 1b– F0/1/2– BL viral load <2,000,000 IU/mL

Conclusions

In poor IFN responders, HCV subtype, fibrosis score, and baseline viral load remain important pre-treatment predictors of SVR.

In addition, virological response at TW8 (4 weeks of PR + 4 weeks of BOC/PR) provides additional information in predicting SVR.

Analysis of Sustained Viral Response and Boceprevir Resistance Following

Combination Treatment With Boceprevir Plus Peginterferon Alfa-2a/Ribavirin

in HCV Genotype 1 Prior Relapsers And Nonresponders

J Howe1, R Ogert1, R Barnard1, D Hazuda1, LD Pedicone1, CA Brass1, JK Albrecht1, and S Flamm2

1Merck, Sharp & Dohme Corp., Whitehouse Station, NJ; 2Northwestern Feinberg School of Medicine, Chicago, IL

Study Design

Stopping Rule

Weeks 12 24 48 72

Placebo + PEG2a/R44 wks

PEG2a/R4 wks

Follow-up24 wks

PEG2a/R ControlN = 67

BOC + PEG2a/R44 wks

BOC/PEG2a/RN = 134

8 36

Lead-in

• Stopping rule: patients with detectable HCV-RNA at week 12 were discontinued from treatment for futility. Undetectable defined as <LLD (9.3 IU/mL)

• Peginterferon alfa-2a administered subcutaneously at 180 μg once weekly plus ribavirin using weight based dosing of 1000-1200 mg/day in a divided daily dose. Boceprevir was administered 800 mg TID

4

Follow-up24 wks

PEG2a/R4 wks

21

33

64

12

0

20

40

60

80

100

SVR Relapse

% o

f Pat

ient

s

Level observed in RESPOND-2trial using PEG2b

SVR and Relapse Rates Are Consistent With RESPOND 2

PEG2a/R

BOC/PEG2a/Rp<0.0001

721

1195

86134

1467

Triple Therapy at Saint Louis University

• Boceprevir, telaprevir approved in the United States in May, 2011

• Between June, 2011 and December, 2011, 130 patients started boceprevir

• 62% males; 12% AA

• 54% advanced fibrosis/cirrhosis

• 58% null responders; 30% partial responders

Triple Therapy at Saint Louis University

Pretreatment HCV RNA 1,606,111 IU/mL

After 4 weeks lead-in 493,197 IU/mL

1 log drop in HCV RNA 50%

IL28B 91% TC/TT

Triple Therapy at Saint Louis University

• 36 patients have completed 8 weeks of treatment

– 44% were HCV RNA non-detected

• 22 patients have completed 12 weeks of treatment

– 46% were HCV RNA non-detected

– 64% were HCV RNA < 1,000 IU/mL

Summary and Conclusions• Triple therapy was generally well-tolerated

– Anemia and dysgeusia occurred more often in the boceprevir groups than the control group

• Boceprevir added to PR significantly increased SVR compared to

PR control – Can be used to treat patients with all categories of interferon

responsiveness

• RGT and BOC/PR 48 were equally effective for treatment failure patients

• PR lead-in allows for real time assessment of patient’s interferon responsiveness– Poorly responsive: 33-34% achieved SVR vs 0% in control– Responsive: 73-79% achieved SVR vs 26% in control