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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