CCO HCV Resistance Slides

Clinical Implications of HCV Resistance
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Faculty
Program Director
Stefan Zeuzem, MD
Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany
Faculty
Graham R. Foster, FRCP, PhD
Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Mary, University of London London, United Kingdom

Faculty Disclosures
Stefan Zeuzem, MD, has disclosed that he has received fees for nonCME services from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche and consulting fees from Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex.
Graham R. Foster, FRCP, PhD, has disclosed that he has received research support from Boeringher Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Novartis, and Roche and has served as a consultant and received fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche.
Introduction

Introduction
PegIFN and RBV was standard-of-care therapy for chronic HCV for several yrs
Treatment difficult to tolerate, but forgiving
Missing or delaying an occasional tablet rarely leads to treatment failure

Cumulative RBV Exposure and SVR: Genotype 1 Treatment Completers

100 80 Response (%) PegIFN alfa-2a 180 g/wk + RBV 1000/1200 mg/day SVR Relapse
67
60 40
62
57
54
P = .0006 for trend CochraneArmitage test between RBV cumulative dose and SVR
32 20 0 19 22
33
> 97 > 80-97 > 60-80 0-60 Cumulative RBV Exposure Levels (%)
Reddy KR, et al. Clin Gastroenterol Hepatol. 2007;5:124-129.

Introduction
Direct-acting antivirals are less forgiving
Boceprevir and telaprevir tablets should be taken every 8 hrs with careful attention to timing and food requirements
Suboptimal therapy may lead to drug resistance
Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.

Drug Resistance Frequent in Patients Failing Boceprevir or Telaprevir

TVR treatment-emergent resistance substitutions in majority of isolates from subjects in phase III studies who did not achieve SVR[1]
Among BOC-treated subjects who did not achieve SVR in phase III studies and for whom samples were analyzed, 53% had 1 treatment-emergent NS3 protease amino acid substitutions[2] Nearly all of these substitutions have been shown to reduce TVR or BOC anti-HCV activity in cell culture or biochemical assays[1,2]
1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011.

Futility Rules for Boceprevir or Telaprevir + PegIFN/RBV

Boceprevir[1,2] Time Point Wk 12 Wk 24
Criteria HCV RNA 100 IU/mL HCV RNA detectable
.
Action Discontinue all therapy Discontinue all therapy
Telaprevir[2,3] Time Point Wk 4 or 12 Wk 24 Criteria HCV RNA > 1000 IU/mL HCV RNA detectable
Action Discontinue all therapy Discontinue pegIFN/RBV
Assay should have a lower limit of HCV RNA quantification of 25 IU/mL and a limit of HCV RNA detection of ~ 10-15 IU/mL.
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.

Stopping RulesThe Theory

Quasispecies with dominant wild-type virus and single resistant variants After ~ 4-24 wks, wild-type virus is eliminated PegIFN/ RBV
PI + PegIFN/RBV
Triple therapy with HCV PI Baseline
Wild type Medium resistance/more fit

Courtesy of Christoph Sarrazin, MD.
High resistance/unfit Resistance with increased fitness

Stopping RulesThe Facts: Multiple Mutations May Be More Troublesome

Loss of detectable resistance in patients with resistant variant(s) at failure of TVR + pegIFN/RBV (analysis includes only patients with follow-up data)
1.0 0.8 Probability 0.6 0.4 0.2 0 0 2 4 V36M alone (n = 22) 6 8 10 12 Mos After Treatment Failure V36M Alone* % of 1a failures (WT: 16%) Median mos to loss (95% CI) Sullivan J, et al. EASL 2011. Abstract 8. 10 6 (4-9) R155K Alone 20 10 (9-13) 14 16 18 R155K alone (n = 41) V36M + R155K (n = 124)
V36M + R155K 46 13 (10-13)
*Comparison of V36M vs V36M + R155K: P < .0001. Comparison of R155K vs V36M + R155K: P = .48.

Loss of Detectable Resistance in Patients Stopping BOC + PegIFN/RBV

Analysis includes only pts with follow-up data and resistant variant(s) at failure
HCV-Resistant Variant
T54A A156S
Patients No Longer Harboring Resistant Variant at Long-term Follow-up (6-14 Mos), %

94 88
V55A
V36M
86
75
R155K
T54S
68
68
Barnard RJ, et al. AASLD 2011. Abstract 164.

Resistance Profile of Approved and Investigational PIs

V36A/M Telaprevir (linear) Boceprevir (linear) T54A V55A Q80R/K R155K/T/Q A156S A156V/T D168A/V/T/H V170A
* *
SCH900518 (linear)
BILN-2061 (macrocyclic) ITMN191 (macrocyclic) MK7009 (macrocyclic) TMC435350 (macrocyclic) BI-201335 (linear) MK5172 (macrocyclic) GS-9256 (macrocyclic) ABT 450 (macrocyclic) BMS-791325 (macrocyclic)
* *
Resistance mutations of NS3 PIs with a and < 4-fold increase in EC50 shown in red and white, respectively. *Mutations associated with resistance in vitro only.
Halfon P, et al. J Hepatol. 2011;55:192-206.

Section 1 Take-Home Points

Stopping rules detailed in prescribing information should be strictly adhered to
Current understanding of PI failure patients
Optimal regimen for retreatment is not yet clear
However, retreatment with current PIs is not recommended
Resistance mutations detected following failure typically decline in frequency following treatment discontinuation until wild-type variants once again predominate
May take many mos
Value of resistance testing at failure not yet clear
In this rapidly moving field, new approaches are currently being developed and assessed in clinical trials

Recommendations for Missed PI Doses

Timing of Missed Dose Boceprevir[1] < 2 hrs before next dose due 2 hrs before next dose due Telaprevir[2] > 4 hrs since dose usually taken < 4 hrs since dose usually taken Skip missed dose and resume regular dosing schedule Take dose immediately and resume regular dosing schedule Skip missed dose and resume regular dosing schedule Take dose immediately and resume regular dosing schedule Action
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.

Minimal Viral Decline With PegIFN Alone, Enhanced With Addition of TVR
Change in HCV RNA From Baseline (log10 IU/mL) 1 0 -1 -2 -3 -4 -5 -6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Days Sequence analysis PegIFN + placebo (n = 4) TVR (n = 8) TVR + PegIFN (n = 8)
Resistance mutations emerged in TVR monotherapy arm within 4-7 days; subsequently suppressed by pegIFN/RBV
Kieffer TL, et al. Hepatology. 2007;46:631-639.

RBV Also Required in PI Combination Regimens

100 80 PROVE-2[1] 100 80 60 SVR (%) 60 50 40 20 36 SPRINT-1[2]
SVR (%)
60
40 20 0
36
12-wk TVR + 12-wk TVR + PegIFN + RBV PegIFN (n = 82) (no RBV) (n = 78)
48-wk BOC + 48-wk BOC + PegIFN + PegIFN + Full-Dose RBV Low-Dose RBV (n = 16) (n = 59)
1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. Kwo PY, et al. Lancet. 2010;376:705-716.

Improved Virologic Response When RBV PegIFN Added to GS-9256 + Tegobuvir

GS-9256: NS3 protease inhibitor
Tegobuvir: nonnucleoside polymerase inhibitor
HCV RNA Response GS-9256 + Tegobuvir (n = 15) GS-9256 + Tegobuvir + RBV (n = 13) GS-9256 + Tegobuvir + PegIFN/RBV (n = 14)
Median maximal change from baseline, log10 IU/mL

Day 14 HCV RNA < 25 IU/mL, % Day 28 HCV RNA < 25 IU/mL (RVR), %
-4.1
-5.1
-5.7
7 7
46 38
71 100
Zeuzem S, et al. Hepatology. 2012;55:749-758.


Guidance is available in package inserts for management of missed doses
Both pegIFN and RBV required in current PI-based combination regimens
Patients should be counseled on the importance of adherence to all components of the treatment regimen

Progression of Fibrosis in Rebiopsied Patients

282 patients with Ishak stage 0 or 1 on initial biopsy rebiopsied[1]
Progression of fibrosis occurred in 42% of pts over median of 52.5 mos
60 Patients (%) 50 40 30
20
10 0 -1 0 1 2 3 4 Change in Fibrosis Score 5
Factors associated with fibrosis progression of 2 Ishak stages: age at first biopsy (P = .001) and median ALT level (P = .007)[1]
Fibrosis progression more rapid in patients coinfected with HIV[2]
1. Williams MJ, et al. J Viral Hepat. 2011;18:17-22. 2. Deng LP, et al. World J Gastroenterol. 2009;15:996-1003.

REALIZE: SVR in Previous Relapsers, Partial Responders, Null Responders

PR48 Previous Relapsers 100 83* 80 88* T12/PR48 LI T12/PR48 Previous Null Responders Previous Partial Responders
SVR (%)
60 40 24 20
n/N=
59*
54* 33*
29* 15
121/ 145 124/ 141
5
29/49 26/48 2/37 21/72 25/75
16/68
4/27
*P < .001 vs PR48.

Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

PROVIDE: BOC-Based Therapy in Previous Null Responders

Limited data on efficacy of BOC in previous null responders because excluded from RESPOND-2 trial
Patients (%) Responses in Previous Null Responders* 100 80 60 40 20
n/N =
Current study: single-arm, multicenter rollover study of pts from pegIFN/RBV arms of phase II/III BOC studies
Current analysis of null responders from RESPOND-2 and SPRINT-2: < 2 log decline in HCV RNA after 12 wks of pegIFN/RBV (N = 52) Pts received 4-wk pegIFN/RBV lead-in followed by 44 wks triple therapy
Bronowicki JP, et al. EASL 2012. Abstract 11.
38 14
19/50 3/22
SVR
Relapse
*2 patients are still receiving treatment. Includes 3 patients who discontinued treatment during lead-in phase.

SVR by Week-4 Response in Lead-in Arms of Treatment-Experienced Trials

100
80 SVR (%) 60 40 20 0
100 76
SVR (%) 80 60 40 20 0
< 1 log decline 1 log decline 82
33
33
RESPOND-2* (BOC)[1]
*Pooled data from RGT and arm 3.
15 REALIZE (TVR)[2] 8
1. Vierling JM, et al. EASL 2011. Abstract 481 2. Foster G, et al. EASL 2011. Abstract 6.

SVR by Response at Wk 4 in Lead-in Arm With Boceprevir and Telaprevir

REALIZE (TVR)[1]
100 80 62 Relapsers 94 Partial NR 100 80 SVR (%) 56 59 64 54 60 40 20
106/ 113 16/27 15/28
PROVIDE (BOC)*[2]
Null NR
72 56 55
SVR (%)
60 40 20
36
15
8/13 10/18 6/41
n/N =
< 1 log
1 log
N/A 14/22 13/36 < 1 log
5/9 36/50 6/11
1 log
*Excludes 4 pts who dropped out during lead-in phase and 8 who were direct enrollers (ie no pegIFN/RBV lead-in). Majority of prior relapsers still receiving treatment.
1. Foster G, et al. EASL 2011. Abstract 6. 2. Bronowicki JP, et al. EASL 2012. Abstract 11.

BMS-790052 + BMS-650032 PegIFN/RBV for 24 Wks in GT1 Null Responders

Combinations of 2 DAAs + pegIFN RBV being evaluated for null responders First published study combines NS5A inhibitor BMS-790052 with NS3 PI BMS-650032
BMS-790052 + BMS-650032 (n = 11) 64 (7) 36 (4) 36 (4) BMS-790052 + BMS-650032 + PR (n = 10) 60 (6) 100 (10) 90 (9)*
Undetectable HCV RNA, % (n) RVR SVR12 SVR24
*1 pt had detectable but not quantifiable HCV RNA levels at Wk 24 after treatment and undetectable HCV RNA levels on retesting 35 days later.
In dual therapy arm, 2/2 GT1b vs 2/9 GT1a pts reached SVR12 and SVR24
6 GT1a pts had breakthrough and resistance to both agents
No viral breakthrough with quadruple therapy BMS-790052 and BMS-650032 alone or + pegIFN/RBV generally well tolerated
Lok AS, et al. N Engl J Med. 2012;366:216-224.


Assessing fibrosis score in previous null responders helpful to determine if treatment should be initiated immediately or if patient can wait for future options
~ 35% of null responders receiving BOC- or TVR-based regimens achieve SVR Response to lead-in period may be helpful in previous null responders to identify patients who are IFN responsive
IFN-nonresponsive patients more likely to fail therapy and develop resistance
New therapies may provide opportunity for higher SVR rates in previous null responders

Reasons to Consider Immediate Treatment

Response rates more favorable in patients with milder vs more advanced disease[1,2]
Chronic HCV infection may impair quality of life[3] New regimens in development might develop unexpected problems
Some promising drugs fail in phase III clinical trials due to unexpected adverse effects
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364: 2405-2416. 3. Foster GR. J Hepatol. 1999;31(suppl 1):250-254.

SVR by Fibrosis/Cirrhosis Stage in Patients Receiving BOC + PegIFN/RBV

Subgroup Analysis of SPRINT-2[1] 100 80 PR48 BOC RGT BOC/PR48 SVR (%) 52 38 38 41 Subgroup Analysis of RESPOND-2[2]
100
80 68 68
67
67
66
SVR (%)
60 40 20
n/ N=
60
44 40 23 20 13
14/ 61 77/ 81/ 117 119 2/ 15 14/ 32 21/ 31
123/ 213/ 211/ 328 319 313
9/ 24
14/ 34
22/ 42
n/ N=
F0/1/2
F3/4
F0/1/2
F3/4
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

SVR by Fibrosis/Cirrhosis Stage in Patients Receiving TVR + PegIFN/RBV

Subgroup Analysis of ADVANCE
100 80 SVR (%) 60 47 40 33 78 73 62 53 PR48 T12PR T8PR
20 0
n/ N= 134/ 288 226/ 290 205/ 279 24/ 73 45/ 73 45/ 85
No, Minimal, or Portal Fibrosis

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Bridging Fibrosis or Cirrhosis

Reasons to Consider Deferring Therapy

Disease progression slow in many patients
Current regimens are complex with many adverse effects If patient is hesitant to begin therapy, may be less adherent
Could lead to outgrowth of resistant variants
New experimental therapies are being developed and may offer similar or better response rates with fewer adverse effects
IFN-free regimens an active focus of research

Current Standard-of-Care Therapy Is Complex

Adherence to pegIFN/RBV therapy decreases over time
100
Triple therapy has greatly increased treatment complexity, involves multiple Treatment daily pills plus injection drug
Wk 0-12 13-24 25-36 37-48
Mean Adherence (%)
100
80 60
95 95
89
97 86 84 76
BOC TID: 12 pills/day TVR TID: 6 pills/day RBV BID: 4-6 pills/day PegIFN: QW injection
40
20 0 PegIFN RBV (N = 5706)
Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Increased risks with nonadherence to triple therapy include potential for resistance

Several Drugs in Development Are Dosed Once or Twice Daily

QD ABT-072 ABT-267 ABT 450* ACH-1625 BI 201335 Daclatasvir GS 5885 GS 9451 IDX 184 INX-189 MK-5172 Narlaprevir* PSI-7977 PSI-938 TMC435 BID ABT-333 Asunaprevir BI 201335 BI 207127 BMS 791325 Danoprevir* Filibuvir GS9256 Mericitabine Setrobuvir Tegobuvir Vaniprevir VX-222 TID BI 207127 Danoprevir
*With ritonavir boosting.


Treatment-naive patients with minimal fibrosis have the best chance for successful therapy
However, these patients can also afford to wait for future regimens
Therefore, if patient is hesitant about initiating therapy, could consider waiting for future options and explaining to patient
Future therapies may have better response rates Future regimens may be less complex Adherence to current regimens critical and if patient is hesitant about starting, may be better to defer therapy rather than risk development of resistant variants through poor adherence

Conclusions
Resistance does occur with the new PI-based antiviral regimens
Careful adherence to the prescribing information may reduce the incidence of resistance
Impact of resistance development on response to future regimens not yet clear

Patients should be counseled about current and future possibilities and informed about the great uncertainties
Go Online for Additional Educational Programs on HCV Resistance

Interactive Virtual Presentation providing expert opinion on how to avoid the development of HCV resistance with new direct-acting antiviral regimens through review of 4 patient cases Expert Dialogue Module of key data and case scenarios on HCV resistance 3 Expert Viewpoints authored by expert faculty to enhance your knowledge of resistance in HCV
clinicaloptions.com/HCVResistance
Highlights From Barcelona 2012

CCO Independent Conference Coverage
of the 47th Annual Meeting of the European Association for the Study of the Liver*
April 18-22, 2012 Barcelona, Spain
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by an educational grant from educational grants from


Highlights From Barcelona 2012

CCO Independent Conference Coverage
of the 47th Annual Meeting of the European Association for the Study of the Liver*
April 18-22, 2012 Barcelona, Spain
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This program is supported by an educational grant from educational grants from

About These Slides

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com)
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty
Graham R. Foster, FRCP, PhD Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Mary, University of London London, United Kingdom David R. Nelson, MD Professor of Medicine Associate Dean for Clinical Research University of Florida College of Medicine Gainesville, Florida Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I J W Goethe University Hospital Frankfurt, Germany

Faculty Disclosures
Graham R. Foster, FRCP, PhD, has disclosed that he has received consulting fees and fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, Roche, and Transgene.
David R. Nelson, MD, has disclosed that he has contracted research with Abbott, Bristol-Myers Squibb, Genentech, Gilead Sciences, Janssen, Merck, and Vertex. Stefan Zeuzem, MD, has disclosed that he has received consulting fees from Abbott, Achillion, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, Roche, Santaris, and Vertex and has received fees for non-CME services from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Roche.

Optimizing HCV Management With Current Therapies

Retrospective Analysis of TVR Ph III Trials Underscores Validity of TVR Futility Rules
No pt with HCV RNA > 1000 IU/mL at Wk 4 (n = 25) or Wk 12 (n = 12) had SVR Viral kinetics analysis of pts with HCV RNA > 1000 IU/mL at Wk 4 23 of 25 reached HCV RNA nadir before Wk 4 In most pts, HCV RNA already increasing from nadir by Wk 4
HCV RNA, IU/mL
Tx Naive (n = 14)
108 107 106 105 104 103 102 10 0 2 4 6 8 10 12
Tx Experienced (n = 11)
108 107 106 105 104 103 102 10 0 2 4 6 8 10 12
Emergence of highly TVR-resistant variants in majority of pts with HCV RNA > 1000 IU/mL at Wk 4
Level of TVR Resistance High High Low None
Wks on Treatment
Wks on Treatment
Tx-Expd Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 11) 8 0 2 1
*1 patient had R155K present at baseline.
HCV NS3/4A Variant V36M + R155K A156S/T/V R155K Wild type
Tx-Naive Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 14) 12* 1 0 1
Jacobson I, et al. EASL 2012. Abstract 55.

PROVIDE: Efficacy of BOC-Based Therapy in Treatment-Experienced Patients

Limited data on efficacy of BOC in previous null responders because excluded from RESPOND-2 trial
Patients (%) 100 80 60 40 20
40 (19/47)
SVR According to Previous Treatment Category*
Current study: single-arm, multicenter rollover study of well characterized pts from pegIFN/RBV arms of phase II/III BOC studies
Current analysis included null responders from RESPOND-2 and SPRINT-2: < 2 log decline in HCV RNA after 12 wks of pegIFN/RBV (N = 52) Pts received 4-wk pegIFN/RBV lead-in followed by 44 wks triple therapy
68 (53/78) 56 (5/9)
Null
Partial
Relapse
Previous Response
*Does not include 4 patients dropping out during lead-in. Adjusted numbers if these patients were included are 38% (19/50) for previous null responders and 50% (5/10) for previous relapsers.
Bronowicki J, et al. EASL 2012. Abstract 11.

Boceprevir + PegIFN/RBV in GT1 HCV TherapyNaive HIV/HCV Coinfection

Randomized 2:1; stratified by cirrhosis/fibrosis and HCV RNA (< vs 800,000 IU/mL)
Wk 4
Wk 48
Wk 72
HIV/genotype 1 HCVcoinfected patients naive to HCV treatment, receiving effective antiretroviral therapy (N = 98)
PegIFN/RBV* lead-in (n = 64)
BOC 800 mg TID + PegIFN/RBV* (n = 64) Follow-up
PegIFN/RBV* lead-in (n = 34)
Placebo + PegIFN/RBV* (n = 34)
*PegIFN 1.5 g/kg/wk; RBV 600-1400 mg/day, according to weight, in divided BID dose. Patients in placebo arm with HCV RNA lower limit of quantification at Wk 24 eligible to receive open-label BOC plus pegIFN/RBV.
Mallolas J, et al. EASL 2012. Abstract 50.

Higher SVR12 Rates With BOC + P/R vs P/R Alone in HIV/HCV Coinfection
Interim efficacy analysis
3 BOC pts had not yet reached SVR12 time point
100 80 SVR12 (%) 60 40 20 0 n/N = 37/61 BOC + P/R 9/34 P/R 60.7*
HIV-1 RNA breakthrough observed in 7 pts

BOC + P/R: n = 3/64 Placebo + P/R: n = 4/34
Tolerability similar to that seen in HCV monoinfection

Similar rates of total and serious adverse events in BOC and placebo groups Higher rates of discontinuation due to toxicity with BOC (20%) vs placebo (9%)
26.5
*Reflects presented data; speaker noted verbally that remaining 3 pts have now reached and achieved SVR12
Caution needed with drug-drug interactions
Mallolas J, et al. EASL 2012. Abstract 50.

Management of Anemia With BOC-Based HCV Therapy: EPO vs RBV Reduction

Nested study within randomized trial of GT1 HCV therapy-naive pts receiving 4 wks lead-in, then either 44 wks triple therapy or response-guided therapy (24-44 wks)
Baseline Hb requirements: 12-15 g/dL for women, 13-15 g/dL for men
Stratified by black vs nonblack, anemia onset 16 wks vs > 16 wks from initiation of lead-in
Pts with Hb 10 g/dL* during BOC-based therapy (N = 500)
RBV Dose Reduction (by 200-400 mg/day) (n = 249)

Erythropoietin 40,000 IU/wk (n = 251)
Secondary anemia management with RBV dose reduction, erythropoietin administration, or transfusion, allowed if Hb 8.5 g/dL Patients discontinued if Hb 7.5 g/dL
*Patients could also be randomly assigned if Hb < 11 g/dL and predicted to be 10 g/dL before next protocol-specified visit. Assessment at 2 wks. Second, third level of dose reduction (each by 200 mg/day) allowed, if required.
Poordad F, et al. EASL 2012. Abstract 1419.

RBV Dose Reduction for First-line Anemia Management Did Not Impact SVR
100 80 SVR (%)
-0.7% (95% CI: -8.6 to 7.2)*
Similar SVR rates with 2 strategies, regardless of baseline characteristics

Subgroup, % Sex Female Male Race Black Nonblack Weight 53 75 72 71 65 70 78 74 58 49 76 70 72 65 67 82 72 67 69 77 72 69 RBV Dose Reduction (n = 249) EPO (n = 251)
71
71
60
40 20 0
n/N =
178/249
178/251
< 75 kg 75 kg IL28B TT CT CC Fibrosis score F0/1/2 F3/4
RBV DR
EPO
*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.
82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia intervention

No Association Between Degree of Hb Decline and SVR in Pts Developing Anemia

RBV DR 100 80 SVR (%) 64 60 40 20
n/N =
EPO
69
61
68
73
72
76
74
7/11 20/29
30/49 49/72
65/89 53/74
76/100 56/76
>3-4 >4-5 Maximum Hb Decline (g/dL)
>5

CUPIC: Interim Analysis of Telaprevir and Boceprevir Use in Cirrhotics

CUPIC: French compassionate use program designed to provide early access to TVR and BOC after completion of phase III trials but before marketing authorization
Patients enrolled at 55 sites beginning February 2011 Genotype 1 HCV, compensated cirrhosis (Child-Pugh A), previous relapse or partial response to pegIFN/RBV 15% to 16% of patients included had esophageal varices; represents a group that did not qualify for inclusion in phase III trials
Interim analysis of patients who received 16 wks of one of the following regimens
TVR-based therapy: TVR 750 mg TID + pegIFN alfa-2a 180 g/wk + RBV 1000-1200 mg/day for 12 wks followed by pegIFN/RBV for 36 wks
Total TVR-based therapy: 140 days; median duration at current analysis: 84 days
BOC-based therapy: 4-wk pegIFN alfa-2b 1.5 g/kg/wk + RBV 800-1400 mg/day lead-in phase followed by BOC 800 mg TID + pegIFN/RBV for 44 wks Total BOC-based therapy: 168 days; median duration at current analysis: 140 days
Hezode C, et al. EASL 2012. Abstract 8.

CUPIC: Efficacy of Telaprevir in Cirrhotics

~ 80% of patients treated with TVR-based therapy had undetectable HCV RNA at end of 12 wks of triple therapy
100 Undetectable HCV RNA (%) 85 80 79 86 78 71 60 53 51 86 Per protocol ITT
40
20 n/ N= 0 145/ 145/ 276 285 Wk 4 224/ 224/ 265 282 Wk 8 219/ 219/ 254 281 Wk 12 177/ 177/ 205 251 Wk 16

CUPIC: Safety of Telaprevir in Cirrhotics

Safety Outcome, % Serious adverse events Premature treatment discontinuation Resulting from serious adverse events Death Telaprevir-Based Therapy (n = 296) 48.6 26.0 14.5 2.0 (sepsis [n = 2], pneumopathy [n = 1], bleeding of esophageal varices [n = 1], encephalopathy [n = 1], and lung carcinoma [n = 1]) 8.8 7.5 4.4
Grade 3/4 nonhematologic adverse events

Infection Rash Hepatic decompensation
Hematologic adverse events and support

Anemia Grade 2 Grade 3/4 19.6 10.1
Use of erythropoietin
Blood transfusion Thrombocytopenia Grade 3/4
56.8
15.2 13.1
Use of thrombopoietin
Neutropenia Grade 3/4 Use of G-CSF
1.7
4.7 2.4

CUPIC: Efficacy of Boceprevir in Cirrhotics

~ 60% of patients treated with boceprevir-based therapy had undetectable HCV RNA at Wk 16 of ongoing therapy
100 Undetectable HCV RNA (%) 80 71 60 61 58 61 Per protocol ITT
40
37
37
20 n/ N= 0
1 55/ 55/ 149 150 Wk 8 88/ 88/ 144 151 Wk 12 89/ 89/ 126 146 Wk 16
2/ 2/ 155 155 Wk 4

CUPIC: Safety of Boceprevir in Cirrhotics

Safety Outcome, % Serious adverse events Premature treatment discontinuation Resulting from serious adverse events Boceprevir-Based Therapy (n = 159) 38.4 23.9 7.4
Death
Grade 3/4 nonhematologic adverse events Infection Rash Hepatic decompensation Hematologic adverse events and support Anemia
1.3 (bronchopulmonary infection [n = 1] and sepsis [n = 1])

2.5 0 4.4
Grade 2
Grade 3/4 Use of erythropoietin Blood transfusion Thrombocytopenia Grade 3/4 Use of thrombopoietin
22.6
10.1 66.0 10.7 6.9 1.9 5.0 3.8
Neutropenia
Grade 3/4 Use of G-CSF

HCV PI Therapy for HCV Recurrence Following Liver Transplantation

Multicenter experience
Active, chronic GT1 HCV infection HCV recurrence: F2 (n = 20) or cholestatic hepatitis (n = 8)
Fibrosis stage F3, % Cholestatic hepatitis, % Characteristic BOC + P/R (n = 17) 53 24 TVR + P/R (n = 11) 55 36
In absence of trial data, pts treated off label with 1 of 3 regimens

P/R lead-in for 4 wks, followed by BOC 800 mg TID + P/R (n = 17) TVR with lead-in (n = 5)
P/R lead-in for 4 wks, followed by TVR 750 mg TID + P/R
Cyclosporine, %
Tacrolimus, % Mycophenolate mofetil, % HCV RNA, log10 IU/mL (range) ALT*, IU/L Total bilirubin, mol/L CrCl, mL/min Neutrophil count, cells/mm3 Platelet count, cells/mm3
65
35 41 7.0 (5.9-8.5) 191 52 83 2900 142,000
45
55 27 7.1 (5.2-8.3) 99 47 73 2100 145,000
TVR without lead-in (n = 6)

TVR 750 mg TID + P/R Coilly A, et al. EASL 2012. Abstract 47.
P = .01

HCV PI Therapy for HCV Recurrence Following Liver Transplantation

100 Complete RVR (%) 80 60 40 20 36 35 Wk 4 Telaprevir Boceprevir
Anemia was very frequent AE

71% with BOC; 55% with TVR > 90% of pts required EPO
1 death in TVR group
0
100 Complete Virologic Response (%) 80 60 40 20
n = 11 Wk 8 70
n = 17
Calcineurin inhibitor dose reductions required

BOC group
Cyclosporine dose 1.3-fold
56
Tacrolimus dose 5.0-fold
TVR group
Cyclosporine dose 4-fold Tacrolimus dose 35-fold
n = 10 n = 16 0 Coilly A, et al. EASL 2012. Abstract 47.

Investigational IFN-Containing HCV Treatment Regimens

Investigational Agents for HCV Discussed in This Slideset

Class Interferons Cyclophilin inhibitor Nucleos(t)ide analogue polymerase inhibitor Nonnucleoside polymerase inhibitor Drugs Peginterferon lambda-1a Alisporivir GS-7977 Mericitabine ABT-072 ABT-333 BI 207127 Tegobuvir ABT-450 Asunaprevir BI 201335 Danoprevir GS-9451 Simeprevir (TMC435) Daclatasvir GS-5885
Protease inhibitor
NS5A inhibitor

EMERGE: PegIFN lambda-1a vs PegIFN alfa-2a in GT 2/3 HCV Treatment-Naive Pts

Interim analysis of randomized, blinded, active-controlled phase IIb trial
Genotyping at baseline
Wk 24
PegIFN lambda-1a 120 g/wk + RBV (n = 29) PegIFN lambda-1a 180 g/wk + RBV (n = 29) PegIFN lambda-1a 240 g/wk + RBV (n = 30) PegIFN alfa-2a 180 g/wk + RBV (n = 30) *All patient numbers pertain only to patients with GT2/3 HCV. Study also included GT1/4 patients, but current analysis limited to GT2/3 HCV. RBV dosed at 800 mg/day for GT2/3 patients. Zeuzem S, et al. EASL 2012. Abstract 10.
Treatment-naive patients infected with genotype 2/3 HCV (N = 118)

EMERGE: Efficacy and Safety Outcomes

SVR rates comparable in pegIFN lambda-1a arms vs pegIFN alfa-2a
100 80 75.9 65.5 60 40 20 0 N = 29 29 30 30 Lambda Lambda Lambda Alfa 120 g 180 g 240 g 180 g 60.0 Adverse Event, % 53.3 HB low: < 10 g/dL or > 3.4 g/dL RBV dose reduction (Hb associated) Neutrophils low: < 750/mm3 Platelets low: < 100,000/mm3 PegIFN dose reduction (hematologic abnormality)
Fewer hematologic AEs and ALT/AST elevations with pegIFN lambda-1

No difference in other AE categories
Lambda 180 g (N = 29) 6.9 0 0 0 0 6.9 Alfa 180 g (N = 30) 44.8 23.3 27.6 24.1 23.3 13.3
SVR24 (%)
PegIFN lambda-1a 180 g dosage chosen for phase III trials
Zeuzem S, et al. EASL 2012. Abstract 10.
ALT/AST > 5 to 10 x ULN

ATOMIC: GS-7977 + PegIFN/RBV in Treatment-Naive GT1 Patients

Interim analysis of randomized, open-label phase II study
Randomized 1:2:3; stratified by IL28B genotype (CC vs non-CC) and HCV RNA ( vs > 800,000 IU/mL)
Wk 12
Wk 24
GS-7977 400 mg QD + PegIFN/RBV (n = 52) Treatment-naive, noncirrhotic patients chronically infected with HCV* (N = 332) GS-7977 400 mg QD + PegIFN/RBV (n = 125) GS-7977 400 mg QD (n = 75) GS-7977 400 mg QD + RBV (n = 75)
GS-7977 400 mg QD + PegIFN/RBV (n = 155)

*All infected with GT1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for enrollment in the 24-wk arm of GS-7977 plus pegIFN/RBV.
Kowdley K, et al. EASL 2012. Abstract 1.

ATOMIC: High Rate of SVR With 12 Wks of GS-7977 + PegIFN/RBV

Wk 4 EOT 100 80 Patients (%) 60 40 20 0 SVR4 SVR12 98 99 92
94 98 94 90
97 99
Virologic relapse rare to date and not associated with primary resistance
92
No S282T mutation observed in 4 patients with relapse assessed by population sequencing
GS-7977 generally well tolerated in combination with pegIFN/RBV

7977 + P/R 12 Wks 7977 + P/R 24 Wks 7977 + P/R 12 + 12 Wks
No serious adverse events attributed to GS-7977
Kowdley K, et al. EASL 2012. Abstract 1.

ASPIRE: Simeprevir (TMC435) + P/R in Treatment-Experienced GT1 Patients

Double-blind, placebo-controlled phase IIb trial
Wk 12
TMC435 100 mg QD + P/R* (n = 66) TMC435 150 mg QD + P/R* (n = 66) Patients with chronic GT1 HCV who failed previous pegIFN/RBV (16% to 20% in each group had F4 fibrosis) (N = 462) TMC435 100 mg QD + P/R* (n = 65) Wk 24 Placebo + P/R* Placebo + P/R* Placebo + P/R* Placebo + P/R* 24-wk follow-up Wk 48
TMC435 150 mg QD + P/R* (n = 68)

TMC435 100 mg QD + P/R* (n = 66) TMC435 150 mg QD + P/R* (n = 65) Placebo + P/R* (n = 66)
*PegIFN alfa-2a 180 g/wk + RBV 1000-1200 mg/day.

ASPIRE: SVR24 Rates According to Previous Response Category

No advantage of extending therapy beyond 12 weeks; dosing groups pooled in subsequent analysis
100 85 80 SVR24 (%) 57 60 40 20 0 n= 27 79 79 37 19 9 23 68 69 16 50 51 46 51
*Pooled.
85
75
Placebo + PR48 TMC435 100 mg* + PR48 TMC435 150 mg* + PR48
Relapsers
Partial Responders
Null Responders
In TMC435 150-mg group, SVR24 rates similar in patients with/without baseline Q80K
Among GT1a patients, SVR24 in 61% of those with Q80K and 66% of those without Q80K
Zeuzem S, et al. EASL 2012. Abstract 2. Lenz O, et al. EASL 2012. Abstract 9.

ASPIRE: Safety Analysis

Hematologic changes similar to placebo
TMC435 associated with mild, transient, asymptomatic increases in bilirubin

170 160 150 140 130 120 110
0 2 4 6 8 12 16 20 24 28 36 42 48 52 72
Bilirubin elevations did not exceed ULN No significant difference in incidence between 100 mg and 150 mg doses
Hb Mean SE of Actual Values of Neutrophils Segmented (giga/L) Neutrophil Count Mean SE of Actual Values of Total Bilirubin (mol/L) 5 4 3 2 1 0
0 2 4 6 8 12 18 20 24 28 36 42 48 52 72
Bilirubin (Total) 25 ULN 20 15 10 5 0

0 2 4 6 8 12 18 20 24 28 36 42 48 52 72
Mean SE of Actual Values of Total Hb (gl/L)
LLN
LLN
Wk Wks 1-12 TMC435 100 mg Wks 12-24 TMC435 100 mg Wks 24-48 TMC435 100 mg
Wk Wks 1-12 TMC435 150 mg Wks 12-24 TMC435 150 mg Wks 24-48 TMC435 150 mg
Wk Placebo PR48

Investigational All-Oral HCV Treatment Regimens

VITAL-1: Alisporivir-Based Therapy for Treatment-Naive GT2/3 Patients

Stratified by HCV RNA and HCV genotype
Wk 4: RVR assessed
Wk 6 RVR: Alisporivir 1000 mg QD
Wk 24
Alisporivir 1000 mg QD (n = 83) Alisporivir 600 mg QD + RBV (n = 84) Alisporivir 800 mg QD + RBV (n = 94) Alisporivir 600 mg QD + PegIFN (n = 39)
No RVR: Alisporivir 600 mg QD + PegIFN/RBV RVR: Alisporivir 600 mg QD + RBV
Treatmentnaive patients with chronic GT2/3 HCV infection (N = 340)
No RVR: Alisporivir 600 mg QD + PegIFN/RBV RVR: Alisporivir 800 mg QD + RBV 800 mg/day No RVR: Alisporivir 600 mg QD + PegIFN/RBV RVR: Alisporivir 600 mg QD + PegIFN 24-wk F/U
No RVR: Alisporivir 600 mg QD + PegIFN/RBV
PegIFN alfa-2a/RBV (n = 40) Pawlotsky JM, et al. EASL 2012. Abstract 1405.
All pts received alisporivir loading dose of 600 mg BID during first wk. PegIFN alfa-2a dosed 180 g/wk. RBV dosed 800 mg/day.

VITAL-1: SVR12 by Per-Protocol Analysis

High SVR rates with alisporivir-based therapy, including IFN-free regimens
However, development of alisporivir currently on hold due to several cases of pancreatitis (with 1 death) in ~ 1800 patients treated to date
Overall SVR12 100 81 80 SVR12 (%) 60 40 20 0

n = 82 ALV1000 84 ALV600 RBV 93 ALV800 RBV 39 ALV600 Peg 40 P/R
SVR12 in Pts Receiving IFN-Free Therapy 100 93 82 80 58 60 40 20 0

n= 17 29 ALV600 RBV 32 ALV800 RBV ALV1000
83
91
81
77
Pawlotsky JM, et al. EASL 2012. Abstract 1405.

Co-Pilot: 12-Wk ABT-450/r + ABT-333 + RBV in Tx-Naive and -Expd GT1 Patients
Interim analysis of nonrandomized, prospective, open-label phase II trial
Wk 12 ABT-450/Ritonavir 250/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD (n = 19) ABT-450/Ritonavir 150/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD (n = 14) ABT-450/Ritonavir 150/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD (n = 17)
Treatment-naive patients infected with genotype 1 HCV (n = 33)
48 wks of follow-up
Treatment-experienced* patients infected with genotype 1 HCV (n = 17)
*Previous null response (< 2 log10 decrease in HCV RNA by Wk 12) or partial response (HCV RNA above limit of detection during treatment)

Co-Pilot: Virologic Outcomes

SVR12 in 94% of treatment-naive and 47% of treatment-experienced patients
Responses independent of IL28B genotype
100 Patients (%) 80 60 40 20 0 ABT-450/r 250/100 mg QD + ABT-333 + RBV Treatment naive (n = 19) ABT-450/r 150/100 mg QD + ABT-333 + RBV Treatment naive (n = 14) ABT-450/r 150/100 mg QD + ABT-333 + RBV Nonresponders (n = 17) 95 95 79 79 93 93 77 59 47 47 RVR eRVR SVR4 SVR12
90
90

Co-Pilot: Safety Outcomes

Most notable laboratory abnormalities: increased bilirubin and creatinine
Hyperbilirubinemia consistent with known effect of ABT-450 on OATP1B1 bilirubin transporter Both cases of increased creatinine resolved without ABT-450 or ABT-333 dose adjustment
Tx Naive, ABT-450/r 250/100 mg + ABT-333 + RBV (n = 19) 15.8 Tx Naive, ABT-450/r 150/100 mg + ABT-333 + RBV (n = 14) 21.4 Tx Experienced, ABT-450/r 150/100 mg + ABT-333 + RBV (n = 17) 0
Laboratory Abnormalities of Interest, % Total bilirubin 2 x ULN
Creatinine 1.5 ULN*

CrCl < 50 mL/min* ALT 5 x ULN
10.5
10.5 5.3
0
0 0
0
0 0
*Creatinine elevations and shortened creatinine clearance occurred in same 2 patients. Poordad F, et al. EASL 2012. Abstract 1399.

INFORM-SVR: Mericitabine + Danoprevir/r + RBV in Treatment-Naive GT1 Patients

Interim analysis of multicenter, randomized, double-blind, parallel-group phase IIb study
Randomization to 12-wk RBV-containing arm and to entire RBV-free arm stopped prematurely because of high relapse rates Wk 12 Wk 24 Wk 36 Wk 48 Follow-up
eRVR2
Tx-naive patients with chronic GT1 HCV (N = 169)
Mericitabine 1000 mg BID + Danoprevir/Ritonavir 100/100 mg BID + Ribavirin 1000-1200 mg/day
Mericitabine + Danoprevir/Ritonavir + Ribavirin Mericitabine + Danoprevir/Ritonavir + Ribavirin
Follow-up
No eRVR2
Follow-up
Follow-up
Mericitabine 1000 mg BID + eRVR2 Danoprevir/Ritonavir 100/100 mg BID + Placebo Mericitabine + Danoprevir/Ritonavir Mericitabine + Danoprevir/Ritonavir Follow-up
No eRVR2
Follow-up
Gane E, et al. EASL 2012. Abstract 1412.

INFORM-SVR: SVR12 Rates According to HCV Subtype and IL28B Genotype

SVR12 rates higher for GT1b, IL28B non-CC patients
SVR12 Rates in Patients Receiving 24 Wks MCB + DNV/r + RBV
100 80 100 80 All (n = 64) GT1a (n = 43) GT1b (n = 21) 76
71
SVR12 (%) 60 41 26 20 n/N = 0 26/64 11/43 15/21 60 50 44 40 32 27 25
40
20
n/N = 0 6/19 4/15 CC 2/4 20/45 7/28 13/17 Non-CC
Overall
Gane E, et al. EASL 2012. Abstract 1412.
IL28B Genotype

Daclatasvir + GS-7977 RBV in Tx-Naive GT1, 2/3 Pts

Wk 1 Wk 24
Daclatasvir + GS-7977 Daclatasvir + GS-7977 (n = 14) Daclatasvir + GS-7977 + Ribavirin (n = 15) GS-7977 (n = 16) Wk 48 Follow-up
A
Treatment-naive patients with GT1a or 1b HCV infection (n = 44)
GS-7977 (n = 15)
B C D E
Follow-up Follow-up
Treatment-naive patients with GT2 or 3 HCV infection (n = 44)
Daclatasvir + GS-7977 Daclatasvir + GS-7977 (n = 14)
Follow-up Follow-up Follow-up
Daclatasvir + GS-7977 + Ribavirin (n = 14)
GS-7977 dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 pts (1000 -1200 mg/day); 800 mg/day for GT 2/3 pts. Sulkowski M, et al. EASL 2012. Abstract 1422.

Daclatasvir + GS-7977 RBV: Efficacy Analysis According to Genotype

Genotype 1a/1b HCV
100 80
Genotype 2/3 HCV

Group A Group B Group C Light: < LOD Dark: < LLOQ and detectable
100 80
100 100 100

87 93 73 93 87 86 93 87 86
100 100 100 100 100 100
100 100 100

88 79 64
100
94 93 93 86 86 88* 88
100 100
86 79
Patients (%)
Patients (%)
Group D Group E Group F Light: < LOD Dark: < LLOQ and detectable
60
60
40
20 n= 0
40
20 n= 0
15 14 15
15 14 15
15 14 15
16 14 14
16 14 14
16 14 14
Wk 4
Wk 24 (EOT)
SVR4
Wk 4
Wk 24 (EOT)
SVR4
mITT analysis, bars not reaching 100% after Wk 4 reflect missing values.
mITT analysis, bars not reaching 100% after Wk 4 reflect missing values. *1 patient required addition of pegIFN-alfa/RBV (tx intensification), 1 patient with relapse at posttreatment Wk 4 2 patients lost to follow-up (following Wk 12 and 24 visits).
Sulkowski M, et al. EASL 2012. Abstract 1422.

SOUND-C2: BI 201335 + BI 207127 RBV in Tx-Naive GT1 Patients

Stratified by HCV subtype and IL28B genotype
Wk 16
Wk 28
Wk 40
BI 201335 120 mg QD + BI 207127 600 mg TID + RBV (n = 81) BI 201335 120 mg QD + BI 207127 600 mg TID + RBV (n = 80) BI 201335 120 mg QD + BI 207127 600 mg TID + RBV (n = 77) BI 201335 120 mg QD + BI 207127 600 mg BID + RBV (n = 78) BI 201335 120 mg QD + BI 207127 600 mg TID, no RBV (n = 46)* Weight-based RBV dosing (1000-1200 mg/day). *Randomization to this arm stopped early due to FDA concerns regarding lack of RBV. Zeuzem S, et al. EASL 2012. Abstract 101.
Tx-naive patients with GT1 HCV (7% to 17% in each group had cirrhosis) (N = 362)
12-wk follow-up for SVR12

SOUND-C2: Efficacy According to Study Arm, HCV Subgenotype, and IL28B

SVR According to IL28B and HCV Subtype (ITT)
100 80 SVR12 (%) 60 40 20 0 0 TID 16 wks RBV TID 28 wks RBV TID 40 wks RBV BID 28 wks RBV TID 28 wks 59 71 61 38 All patients 1a non-CC All 1b and 1a-CC 82 71
62
56 42
68 53 39 32
32

SOUND-C2: With BID Dosing, Higher SVR12 in Pts With GT1b or GT1a-IL28B CC
SVR According to IL28B and HCV Subtype: BID 28 Wks + RBV (ITT)
100 84 80 SVR12 (%) 60 40 32 75 82
20
n/N = 0 1a non-CC 1a CC 1b non-CC 7/22 6/8 31/37 9/11 1b CC
HCV Subtype and IL28B Genotype Zeuzem S, et al. EASL 2012. Abstract 101.

SOUND-C2 Subanalysis: Efficacy and Safety in Pts With Compensated Cirrhosis

37 (10%) of 362 patients in SOUND-C2 had compensated cirrhosis
SVR12 rates higher for GT 1b pts; impact of IL28B could not be assessed due to small numbers
SVR12 According to HCV GT 100 80 SVR (%) 60 40 3/7 9/14 TID 16, 28, 40 wks* RBV 43 33 2/6 5/7 BID 28 wks RBV 33 0/0 1/3 TID 28 wks 64 71 GT1a GT1b
20 n/N = 0
*SVR12 data not yet available for TID 40 wk arm, so SVR4 rates used in analysis.
Favorable safety with BID dosing, higher rates of discontinuation and serious AEs with TID dosing
Soriano V, et al. EASL 2012. Abstract 1420.

Pilot: ABT-450/r + ABT-072 + RBV in Treatment-Naive GT1 HCV, IL28B CC Pts

Single-arm, open-label, pilot study: ABT-450/r 150/100 mg QD + ABT-072 400 mg QD + weightbased RBV 1000-1200 mg/day for 12 wks
100 80 Patients (%) 100 100 91 91
100% of pts achieved primary endpoint of eRVR; 91% went on to SVR12 and SVR24 2 relapses posttherapy 1 at posttreatment Wk 12; resistance variant observed only in protease
D168V variant observed in 36% of clones sequenced
60
40 20 0 RVR eRVR
1 late relapse at posttreatment Wk 36; resistance variant observed only in polymerase

SVR12
SVR24
Y448H variant observed in 99% of clones sequenced
Lawitz E, et al. EASL 2012. Abstract 13.

4-Drug Therapy With GS-5885, GS-9451, Tegobuvir, and RBV in Tx-Naive GT1 HCV
Interim analysis of randomized phase II study
Wk 2* Wk 12 Wk 24
Randomized 1:2; stratified by HCV RNA ( vs > 800,000 IU/mL) and HCV 1 subtype (1a vs 1b)
Tx-naive patients with chronic GT1 HCV infection (N = 140)
GS-5885 30 mg QD + GS-9451 200 mg QD + Tegobuvir 30 mg BID + Ribavirin (n = 46) GS-5885 90 mg QD + GS-9451 200 mg QD + Tegobuvir 30 mg BID + Ribavirin (n = 94)
Follow-up Rerandomized
Follow-up for SVR24
*Patients with HCV RNA 25 IU/mL at Wk 2 offered rescue therapy including pegIFN or study discontinuation. Patients rerandomized if HCV RNA < 25 IU/mL at Wks 2-10. Sulkowski M, et al. EASL 2012. Abstract 1421.
GS-5885 90 mg QD + GS-9451 200 mg QD + Tegobuvir 30 mg BID + Ribavirin

All-Oral 4-Drug Therapy: Virologic Response and Virologic Breakthrough

Four-drug regimen provided high rates of SVR12 in noncirrhotic patients with GT1 HCV infection
81% with 12-wk therapy (n = 21) Interim analysis; data collection on 24-wk therapy ongoing
Virologic breakthrough, relapse rates lower in GT1b vs 1a infection

Virologic breakthrough associated with emergence of multidrug resistance
Lower virologic breakthrough rates with IL28B CC vs non-CC genotype Well tolerated over 24 wks of treatment
Sulkowski M, et al. EASL 2012. Abstract 1421.

Daclatasvir + Asunaprevir in GT1b Pts With IFN Intolerance or Null Response

24 wks of daclatasvir 60 mg QD + asunaprevir 200 mg BID (N = 43)
10 pts received asunaprevir 600 mg BID
Null responders (n = 21) Ineligible/intolerant (n = 22) HCV RNA Undetectable (%) 100 80 60 40 20
n/N = 11/ 19/ 21 22 19/ 20/ 21 22 19/ 19/ 21 22 19/ 14/ 21 22 19/ 14/ 21 22
Among pts with virologic breakthrough (7.0%) or relapse (9.3%), almost all had trough daclatasvir and asunaprevir plasma concentrations below median
ASV and DCV Trough Plasma Concentrations in Patients With SVR or Virologic Failure Median 201 SVR Relapse Breakthrough
Note: Multiple determination are shown for some patients. *Pharmacokinetic values from a single patient with documented noncompliance after sampling.
86
91 91
91 86
91 64
91 64 Asunaprevir Ctrough (ng/mL)
52
800 600 400 200 100
Virologic failures * * Median 57 100 200 400 600 800 1000 Daclatasvir Ctrough (ng/mL)
Wk 4 RVR
SVR12 Wk 12 End of cEVR Treatment*
SVR24
*End of treatment = Wk 24 or last on-treatment visit for pts who discontinued early. ITT (missing = failure) analysis.
Suzuki F, et al. EASL 2012. Abstract 14.

DAUPHINE: Danoprevir/r + PegIFN/RBV in GT1/4 Treatment-Naive Patients

Interim analysis of multicenter, randomized, open-label phase IIb study Wk 24 Wk 12 Danoprevir/Ritonavir 200/100 mg q12h + P/R (n = 94) Danoprevir/Ritonavir 100/100 mg q12h + P/R (n = 93) Danoprevir/Ritonavir 50/100 mg q12h + P/R (n = 94) Danoprevir/r 100/100 mg q12h + P/R* (n = 94) Follow-up for SVR24 Wk 36 Wk 48 Wk 60
Treatment-naive pts with GT1/4 HCV infection, F0-2 fibrosis, HCV RNA 50,000 IU/mL (N = 421)
DNV/r 100/100 mg q12h + P/R
P/R (rollover offered to patients without cEVR)

Rollover Everson G, et al. EASL 2012. Abstract 1177. DNV/r 200/100 mg q12h + P/R P/R
*Stopped all therapy at Wk 12 if eRVR2 (HCV RNA < 15 IU/mL at Wks 2-10); continued to Wk 24 if no eRVR2.

DAUPHINE: Preliminary SVR12 Rates in Pts Treated for 24 Wks With DNV/r + P/R
SVR12 rates increased with higher doses of DNV/r
100 86 80 SVR12 (ITT), (%) DNV/r 200 mg + P/R DNV/r 100 mg + P/R DNV/r 50 mg + P/R 65 60
77
40
20
0 n/N = 79/92 72/93 61/94
Everson G, et al. EASL 2012. Abstract 1177.

Hepatocellular Carcinoma

Brivanib in Pts With Advanced HCC With Progression on or Intolerance to Sorafenib

BRISK-PS: multinational, randomized, double-blind, placebo-controlled phase III trial
Patients randomized to brivanib 800 mg QD (n = 263) or placebo (n = 132), each with supportive care
No improvement in OS in patients with advanced HCC who failed sorafenib

Overall Survival
Brivanib Placebo Events/patients, n 183/263 101/132 Median OS, mos 9.4 8.2 HR (95.8% CI)* 0.89 (0.69-1.15) P (stratified log rank) .3307
Time to Progression
1.0 Probability Alive 0.8 0.6 0.4 0.2 0
1.0 Probability of Progression 0.8 0.6 0.4 0.2 0

2 4 0 Pts at Risk, n 263 144 92 Brivanib 132 45 21 Placebo
Brivanib Placebo Events/patients, n 151/263 75/132 Median TTP, mos 4.2 2.7 HR (95% CI) 0.56 (0.42-0.78) P (log rank) .0001
6 37 6 8 20 5 10 9 2 12 14 2 1 16 18 1 1 0 1 20 0 1 22 0 1 24 0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Pts at Risk, n Brivanib 263 239 208 163 134 95 77 55 40 30 17 12 5 2 0 0 Placebo 132 117 94 75 64 49 35 25 19 16 11 7 4 3 2 0 *95.8% CI adjusted for interim analysis
Mos
3 1
Llovet J, et al. EASL 2012. Abstract 1398.

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V36M + R155K 46 13 (10-13)

Clinical Implications of HCV Resistance

Loss of Detectable Resistance in Patients Stopping BOC + PegIFN/RBV

Patients No Longer Harboring Resistant Variant at Long-term Follow-up (6-14 Mos), %

Barnard RJ, et al. AASLD 2011. Abstract 164.

Clinical Implications of HCV Resistance

Resistance Profile of Approved and Investigational PIs

Halfon P, et al. J Hepatol. 2011;55:192-206.

Clinical Implications of HCV Resistance

Section 1 Take-Home Points

Value of resistance testing at failure not yet clear

Clinical Implications of HCV Resistance

Recommendations for Missed PI Doses

Clinical Implications of HCV Resistance

Clinical Implications of HCV Resistance

RBV Also Required in PI Combination Regimens

Clinical Implications of HCV Resistance

Improved Virologic Response When RBV PegIFN Added to GS-9256 + Tegobuvir

Median maximal change from baseline, log10 IU/mL

Zeuzem S, et al. Hepatology. 2012;55:749-758.

Clinical Implications of HCV Resistance

Section 2 Take-Home Points

Clinical Implications of HCV Resistance

Progression of Fibrosis in Rebiopsied Patients

Clinical Implications of HCV Resistance

REALIZE: SVR in Previous Relapsers, Partial Responders, Null Responders

*P < .001 vs PR48.

Clinical Implications of HCV Resistance

PROVIDE: BOC-Based Therapy in Previous Null Responders

Clinical Implications of HCV Resistance

SVR by Week-4 Response in Lead-in Arms of Treatment-Experienced Trials

< 1 log decline 1 log decline 82

Clinical Implications of HCV Resistance

SVR by Response at Wk 4 in Lead-in Arm With Boceprevir and Telaprevir

N/A 14/22 13/36 < 1 log

5/9 36/50 6/11

Clinical Implications of HCV Resistance