cco hcv resistance slides[1]

Clinical Implications of HCV Resistance

This program is supported by an educational grant from

clinicaloptions.com/hepatitisClinical Implications of HCV Resistance

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These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])

DisclaimerThe 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

Program Director

Stefan Zeuzem, MDProfessor of Medicine Chief, Department of Medicine I

JW Goethe University Hospital Frankfurt, Germany

Faculty

Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Mary, University of LondonLondon, United Kingdom


Faculty Disclosures

Stefan Zeuzem, MD, has disclosed that he has received fees for non-CME 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

PegIFN alfa-2a 180 g/wk + RBV 1000/1200 mg/day100

0

20

40

60

80

> 97 > 80-97 > 60-80 0-60

SVRRelapse

P = .0006 for trend

Cochrane-Armitage test between RBV cumulative dose and SVR

5762

33

67

32

22

54

19

Cumulative RBV Exposure Levels (%)

Res

po

nse

(%

)

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

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [package insert]. May 2011.

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.

Boceprevir[1,2] .

Time Point Criteria Action

Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue all therapy

Telaprevir[2,3] .

Time Point Criteria Action

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue pegIFN/RBV


Stopping Rules—The Theory

Courtesy of Christoph Sarrazin, MD.

Quasispecies with dominantwild-type virus and

single resistant variants

After ~ 4-24 wks,wild-type virus is

eliminated

PegIFN/RBV

PI + PegIFN/RBV

Baseline

Triple therapywith HCV PI

Wild typeMedium resistance/more fit

High resistance/unfitResistance with increased fitness


Stopping Rules—The 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)

V36M Alone* R155K Alone† V36M + R155K

% of 1a failures (WT: 16%) 10 20 46

Median mos to loss (95% CI) 6 (4-9) 10 (9-13) 13 (10-13)

Pro

bab

ilit

y

Mos After Treatment Failure

R155K alone (n = 41)

R155K alone (n = 41)

V36M alone (n = 22)

V36M alone (n = 22)

V36M + R155K (n = 124)V36M + R155K (n = 124)

0.2

0.4

0.6

0.8

1.0

00 2 4 6 8 10 12 14 16 18

Sullivan J, et al. EASL 2011. Abstract 8.

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

T54A 94

A156S 88

V55A 86

V36M 75

R155K 68

T54S 68

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


Resistance Profile of Approved and Investigational PIs

*Mutations associated with resistance in vitro only.

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

Resistance mutations of NS3 PIs with a ≥ and < 4-fold increase in EC50 shown in red and white, respectively.

V36A/M T54A V55A Q80R/K R155K/T/Q A156S A156V/T D168A/V/T/H V170A

Telaprevir (linear) * *

Boceprevir (linear) *

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)


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

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.

Timing of Missed Dose Action

Boceprevir[1]

< 2 hrs before next dose due Skip missed dose and resume regular dosing schedule

≥ 2 hrs before next dose due Take dose immediately and resume regular dosing schedule

Telaprevir[2]

> 4 hrs since dose usually taken Skip missed dose and resume regular dosing schedule

< 4 hrs since dose usually taken Take dose immediately and resume regular dosing schedule


Minimal Viral Decline With PegIFN Alone, Enhanced With Addition of TVR

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.

1Sequence analysis

-6

-5

-4

-3

-2

-1

0

1 2 3 4 5 6 7 8 9 10 11 12 13 14Days

Ch

ang

e in

HC

V R

NA

Fro

m

Bas

elin

e (l

og

10 I

U/m

L)

TVR + PegIFN

(n = 8)

TVR (n = 8)

PegIFN + placebo (n = 4)

15


RBV Also Required in PI Combination Regimens

PROVE-2[1]

SV

R (

%)

0

20

40

60

80

100

48-wk BOC +PegIFN +

Full-Dose RBV(n = 16)

48-wk BOC + PegIFN +

Low-Dose RBV(n = 59)

SPRINT-1[2]

12-wk TVR + PegIFN + RBV

(n = 82)

12-wk TVR + PegIFN (no RBV)(n = 78)

SV

R (

%)

0

20

40

60

80

100

60

36

50

36

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

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

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

-4.1 -5.1 -5.7

Day 14 HCV RNA < 25 IU/mL, %

7 46 71

Day 28 HCV RNA < 25 IU/mL (RVR), %

7 38 100



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

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.

-1Change in Fibrosis Score0 1 2 3 4 5

0

10

Pat

ien

ts (

%)

20

30

40

50

60


100

0

60

SV

R (

%)

80

40

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

Previous Relapsers Previous Partial Responders

n/N=

Previous Null Responders

*P < .001 vs PR48.

20121/145

124/141

83*88*

16/68

24

29/49 26/48

59*54*

4/27

15

21/72 25/75

29*33*

2/37

5

T12/PR48PR48 LI T12/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

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.

*2 patients are still receiving treatment. †Includes 3 patients who discontinued treatment during lead-in phase.

Responses in Previous Null Responders*

100

80

60

40

20

0

38

14

3/2219/50

SVR† Relapse

Pat

ien

ts (

%)

n/N =


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

1. Vierling JM, et al. EASL 2011. Abstract 481 2. Foster G, et al. EASL 2011. Abstract 6.

≥ 1 log decline< 1 log decline

0

20

40

60

80

100

SV

R (

%)

33

REALIZE (TVR)[2]

82

158

*Pooled data from RGT and arm 3.

0

20

40

60

80

100

SV

R (

%)

33

RESPOND-2* (BOC)[1]

76


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

1. Foster G, et al. EASL 2011. Abstract 6. 2. Bronowicki JP, et al. EASL 2012. Abstract 11.

Partial NRRelapsers Null NR

N/A

56†64

72

36

55

0

20

40

60

80

100

SV

R (

%)

< 1 log ≥ 1 log

PROVIDE (BOC)*[2]

n/N = 14/22 13/36 5/9 36/50 6/11

*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.

REALIZE (TVR)[1]

62

94

56 59

15

54

0

20

40

60

80

100

SV

R (

%)

< 1 log ≥ 1 log

8/13 10/18106/113 16/2715/286/41


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

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.

Undetectable HCV RNA, % (n)

BMS-790052 + BMS-650032(n = 11)

BMS-790052 + BMS-650032 + PR(n = 10)

RVR 64 (7) 60 (6)

SVR12 36 (4) 100 (10)

SVR24 36 (4) 90 (9)*

*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.



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]

PR48BOC RGTBOC/PR48

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.

F3/4

100

80

60

40

20

0

SV

R (

%)

F0/1/2

38

67

213/319

n/N =

38

9/24

52

22/42

41

14/34

211/313

67

F3/4

100

80

60

40

20

0

SV

R (

%)

F0/1/2

23

66

77/117

132/15

68

21/31

44

14/32

81/119

68

Subgroup Analysis of RESPOND-2[2]

123/328

n/N =

14/61


PR48T12PRT8PR

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

78

62

73

5347

33

0

20

40

60

80

100

No, Minimal, or Portal Fibrosis

Bridging Fibrosis or Cirrhosis

SV

R (

%)

134/288

n/N =

226/290

205/279

24/73

45/73

45/85

Subgroup Analysis of ADVANCE

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


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 Triple therapy has greatly

increased treatment complexity, involves multiple daily pills plus injection drug

– BOC TID: 12 pills/day

– TVR TID: 6 pills/day

– RBV BID: 4-6 pills/day

– PegIFN: QW injection

Increased risks with nonadherence to triple therapy include potential for resistance

Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

Treatment Wk

(N = 5706)

100

80

60

40

20

0PegIFN RBV

1000-1213-2425-3637-48

959589

9786 84

76

Mea

n A

dh

eren

ce (

%)


Several Drugs in Development Are Dosed Once or Twice Daily

*With ritonavir boosting.

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



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 ResistanceInteractive 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

http://www.clinicaloptions.com/HCVResistance

April 18-22, 2012Barcelona, Spain

Highlights From Barcelona 2012CCO Independent Conference Coverage of the 47th Annual Meeting of the European Association for the Study of the Liver*


*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 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 [email protected])

DisclaimerThe 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, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Mary, University of LondonLondon, United Kingdom

David R. Nelson, MDProfessor of MedicineAssociate Dean for Clinical ResearchUniversity of Florida College of MedicineGainesville, Florida

Stefan Zeuzem, MDProfessor of MedicineChief, Department of Medicine IJ W Goethe University HospitalFrankfurt, 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

Emergence of highly TVR-resistant variants in majority of pts with HCV RNA > 1000 IU/mL at Wk 4

Jacobson I, et al. EASL 2012. Abstract 55.

HCV NS3/4A Variant

Level of TVRResistance

Tx-Naive Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 14)

Tx-Exp’d Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 11)

V36M + R155K High 12* 8

A156S/T/V High 1 0

R155K Low 0 2

Wild type None 1 1

*1 patient had R155K present at baseline.

Tx Experienced (n = 11)Tx Naive (n = 14)

Wks on Treatment0 2 4 6 8 10 12

10

102

103

104

105

106

107

108

0 2 4 6 8 10 1210

102

103

104

105

106

107

108

HC

V R

NA

, IU

/mL

Wks on Treatment


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

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

Bronowicki J, et al. EASL 2012. Abstract 11.

SVR According to Previous Treatment Category*100

80

60

40

20

0

40 (19/47)

68 (53/78)

56 (5/9)

Null Partial Relapse

Pat

ien

ts (

%)

*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.

Previous Response


Boceprevir + PegIFN/RBV in GT1 HCV Therapy–Naive HIV/HCV Coinfection

Mallolas J, et al. EASL 2012. Abstract 50.

BOC 800 mg TID + PegIFN/RBV*

(n = 64)

Placebo† + PegIFN/RBV*(n = 34)

HIV/genotype 1 HCV–coinfected patients naive to HCV treatment,

receiving effective antiretroviral

therapy

(N = 98)

*PegIFN 1.5 µg/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.

PegIFN/RBV*lead-in(n = 64)

PegIFN/RBV*lead-in(n = 34)

Randomized 2:1; stratified by cirrhosis/fibrosis and HCV RNA

(< vs ≥ 800,000 IU/mL) Wk 4 Wk 48 Wk 72

Follow-up


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

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%)

Caution needed with drug-drug interactions

0

20

40

60

80

100

SV

R12

(%

)

P/R

n/N = 9/34

26.5

37/61

60.7*

BOC + P/R

*Reflects presented data; speaker noted verbally that remaining 3 pts have now reached and achieved SVR12

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

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

Poordad F, et al. EASL 2012. Abstract 1419.

Pts with Hb 10 g/dL* during BOC-based

therapy(N = 500) Erythropoietin 40,000 IU/wk

(n = 251)

RBV Dose Reduction (by 200-400 mg/day)†

(n = 249)

*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.

Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks

from initiation of lead-in


RBV Dose Reduction for First-line Anemia Management Did Not Impact SVR

82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia intervention

Similar SVR rates with 2 strategies, regardless of baseline characteristics


Subgroup, % RBV Dose Reduction(n = 249)

EPO(n = 251)

Sex

Female 69 72 Male 77 69

Race

Black 53 49 Nonblack 75 76

Weight

< 75 kg 72 70 ≥ 75 kg 71 72

IL28B

TT 65 65 CT 70 67 CC 78 82

Fibrosis score

F0/1/2 74 72 F3/4 58 67

0

20

40

80

100

SV

R (

%)

RBV DR EPO

∆ -0.7% (95% CI: -8.6 to 7.2)*

71 71

178/249 178/251n/N =

*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.

60


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


n/N =0

20

40

80

100

SV

R (

%)

Maximum Hb Decline (g/dL)

60

7/11 20/29 30/49 49/72 65/89 53/74 76/100 56/76

6469

6168

73 72 76 74

≤ 3 > 3 - ≤ 4 > 4 - ≤ 5 > 5

RBV DR EPO


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 µg/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 µg/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


0

20

40

80

100

Un

det

ecta

ble

HC

V R

NA

(%

)

60

145/276

53

Wk 4 Wk 8 Wk 12 Wk 16

145/285

224/265

224/282

219/254

219/281

177/205

177/251

51

8579

8678

86

71

Per protocolITT

n/N =


CUPIC: Safety of Telaprevir in Cirrhotics


Safety Outcome, % Telaprevir-Based Therapy (n = 296)

Serious adverse events 48.6

Premature treatment discontinuation 26.0

Resulting from serious adverse events 14.5

Death 2.0 (sepsis [n = 2], pneumopathy [n = 1], bleeding of esophageal varices [n = 1], encephalopathy [n = 1], and lung carcinoma [n = 1])

Grade 3/4 nonhematologic adverse events

Infection 8.8

Rash 7.5

Hepatic decompensation 4.4

Hematologic adverse events and support

Anemia

• Grade 2 19.6

• Grade 3/4 10.1

• Use of erythropoietin 56.8

• Blood transfusion 15.2

Thrombocytopenia

• Grade 3/4 13.1

• Use of thrombopoietin 1.7

Neutropenia

• Grade 3/4 4.7

• Use of G-CSF 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


0

20

40

80

100

60

2/155

1

Wk 4 Wk 8 Wk 12 Wk 16

2/155

55/149

55/150

88/144

88/151

89/126

89/146

1

37 37

61 58

71

61

Per protocolITT

Un

det

ecta

ble

HC

V R

NA

(%

)

n/N =


CUPIC: Safety of Boceprevir in Cirrhotics


Safety Outcome, % Boceprevir-Based Therapy (n = 159)

Serious adverse events 38.4

Premature treatment discontinuation 23.9 Resulting from serious adverse events 7.4

Death 1.3 (bronchopulmonary infection [n = 1] and sepsis [n = 1])

Grade 3/4 nonhematologic adverse events

Infection 2.5 Rash 0 Hepatic decompensation 4.4

Hematologic adverse events and support

Anemia

• Grade 2 22.6

• Grade 3/4 10.1

• Use of erythropoietin 66.0

• Blood transfusion 10.7 Thrombocytopenia

• Grade 3/4 6.9

• Use of thrombopoietin 1.9 Neutropenia

• Grade 3/4 5.0

• Use of G-CSF 3.8


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)

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

– 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

Anemia was very frequent AE

– 71% with BOC; 55% with TVR

– > 90% of pts required EPO

1 death in TVR group

Calcineurin inhibitor dose reductions required

– BOC group

– Cyclosporine dose ↓ 1.3-fold

– Tacrolimus dose ↓ 5.0-fold

– TVR group

– Cyclosporine dose ↓ 4-fold

– Tacrolimus dose ↓ 35-fold

Wk 4

36 35

0

20

40

60

80

100

n = 11 n = 17

Co

mp

lete

RV

R (

%)

100Wk 8

56

70

n = 10 n = 160

20

40

60

80

Co

mp

lete

Vir

olo

gic

R

esp

on

se (

%)

Coilly A, et al. EASL 2012. Abstract 47.

TelaprevirBoceprevir


Investigational IFN-Containing HCV Treatment Regimens


Investigational Agents for HCV Discussed in This SlidesetClass Drugs

Interferons Peginterferon lambda-1a

Cyclophilin inhibitor Alisporivir

Nucleos(t)ide analogue polymerase inhibitor GS-7977Mericitabine

Nonnucleoside polymerase inhibitor ABT-072ABT-333BI 207127 Tegobuvir

Protease inhibitor ABT-450AsunaprevirBI 201335 DanoprevirGS-9451Simeprevir (TMC435)

NS5A inhibitor DaclatasvirGS-5885


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

Zeuzem S, et al. EASL 2012. Abstract 10.

Treatment-naive patients infected with

genotype 2/3 HCV(N = 118)

PegIFN lambda-1a 120 µg/wk + RBV†

(n = 29)

PegIFN lambda-1a 180 µg/wk + RBV† (n = 29)

PegIFN lambda-1a 240 µg/wk + RBV† (n = 30)

Wk 24Genotyping at baseline

*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.

PegIFN alfa-2a 180 µg/wk + RBV† (n = 30)


SVR rates comparable in pegIFN lambda-1a arms vs pegIFN alfa-2a

PegIFN lambda-1a 180 μg dosage chosen for phase III trials

EMERGE: Efficacy and Safety Outcomes

Fewer hematologic AEs and ALT/AST elevations with pegIFN lambda-1

– No difference in other AE categories


SV

R24

(%

)

0

40

60

80

100

65.5

20

75.9

60.053.3

N = 29 29 30 30

Lambda120 µg

Lambda180 µg

Lambda240 µg

Alfa180 µg

Adverse Event, %Lambda180 µg(N = 29)

Alfa180 µg(N = 30)

HB low: < 10 g/dL or ∆ > 3.4 g/dL

6.9 44.8

RBV dose reduction(Hb associated)

0 23.3

Neutrophils low: < 750/mm3 0 27.6

Platelets low:< 100,000/mm3 0 24.1

PegIFN dose reduction(hematologic abnormality)

0 23.3

ALT/AST > 5 to 10 x ULN 6.9 13.3


ATOMIC: GS-7977 + PegIFN/RBV in Treatment-Naive GT1 Patients Interim analysis of randomized, open-label phase II study

Kowdley K, et al. EASL 2012. Abstract 1.

Treatment-naive, noncirrhotic

patients chronically infected with HCV*

(N = 332)

GS-7977 400 mg QD +PegIFN/RBV

(n = 52)

GS-7977 400 mg QD + PegIFN/RBV(n = 125)

GS-7977 400 mg QD +PegIFN/RBV

(n = 155)

Wk 24Wk 12Randomized 1:2:3; stratified by

IL28B genotype (CC vs non-CC) and HCV RNA (≤ vs > 800,000 IU/mL)

GS-7977 400 mg QD(n = 75)

GS-7977 400 mg QD +RBV

(n = 75)*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.


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

Virologic relapse rare to date and not associated with primary resistance

– No S282T mutation observed in 4 patients with relapse assessed by population sequencing

GS-7977 generally well tolerated in combination with pegIFN/RBV

– No serious adverse events attributed to GS-7977

Kowdley K, et al. EASL 2012. Abstract 1.

Pat

ien

ts (

%)

0

40

60

80

100

20

7977 + P/R12 + 12 Wks

7977 + P/R12 Wks

7977 + P/R24 Wks

9498 94 9098 99

929799

92

Wk 4EOT

SVR4SVR12


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

placebo-controlled phase IIb trial


Patients with chronic GT1 HCV who failed

previous pegIFN/RBV(16% to 20% in each group had F4 fibrosis)

(N = 462)

Wk 48Wk 12 Wk 24

TMC435 150 mg QD + P/R*(n = 68) Placebo + P/R*

24-wk

follow-up




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 µg/wk + RBV 1000-1200 mg/day.


ASPIRE: SVR24 Rates According to Previous Response Category

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.

80

SV

R24

(%

)

0

40

60

100

20

Relapsers Partial Responders Null Responders

37

85 85

9

57

75

19

4651

27 79 79 23 68 69 16 50 51n =

No advantage of extending therapy beyond 12 weeks; dosing groups pooled in subsequent analysis

TMC435 100 mg* + PR48TMC435 150 mg* + PR48

Placebo + PR48

*Pooled.


ASPIRE: Safety Analysis


Hematologic changes similar to placebo

TMC435 associated with mild, transient, asymptomatic increases in bilirubin

– Bilirubin elevations did not exceed ULN

– No significant difference in incidence between 100 mg and 150 mg doses

110

130

140

150

160

120

Wk

Me

an

± S

E o

f A

ctu

al

Va

lue

s

of

To

tal

Hb

(g

l/L

)

170

0 246 8 12 16 20 2428 36 42 48 52 72

Wks 1-12 TMC435 100 mgWks 12-24 TMC435 100 mgWks 24-48 TMC435 100 mg

Wks 1-12 TMC435 150 mgWks 12-24 TMC435 150 mgWks 24-48 TMC435 150 mg

Placebo PR48

LLN

Hb Neutrophil Count Bilirubin (Total)

LLN

ULN

0

1

2

3

4

Wk

Me

an

± S

E o

f A

ctu

al

Va

lue

s o

f N

eu

tro

ph

ils

Se

gm

en

ted

(g

iga

/L)

0 24 6 8 12 18 20 2428 36 42 48 52 72

0

10

15

20

5

Wk

Me

an

± S

E o

f A

ctu

al

Va

lue

s

of

To

tal

Bil

iru

bin

(μ

mo

l/L

)

0 246 8 12 18 20 2428 36 42 48 52 72

5 25


Investigational All-Oral HCV Treatment Regimens


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

Pawlotsky JM, et al. EASL 2012. Abstract 1405.

Treatment-naive patients with chronic GT2/3 HCV

infection (N = 340)

Alisporivir 1000 mg QD(n = 83)

Alisporivir 600 mg QD + RBV(n = 84)

Alisporivir 800 mg QD + RBV (n = 94)

Wk 24Stratified by HCV RNA and HCV genotype

Alisporivir 600 mg QD + PegIFN(n = 39)

PegIFN alfa-2a/RBV (n = 40)

All pts received alisporivir loading dose of 600 mg BID during first wk. PegIFN alfa-2a dosed 180 µg/wk. RBV dosed 800 mg/day.

Wk 4: RVR assessed Wk 6

24-wkF/U

Alisporivir 600 mg QD + PegIFN/RBV

Alisporivir 1000 mg QD


Alisporivir 600 mg QD + RBV


Alisporivir 800 mg QD + RBV 800 mg/day


Alisporivir 600 mg QD + PegIFN

RVR:

No RVR:

RVR:

No RVR:

RVR:

No RVR:

RVR:

No RVR:


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

Pawlotsky JM, et al. EASL 2012. Abstract 1405.

Overall SVR12 SVR12 in Pts Receiving IFN-Free Therapy

SV

R12

(%

)

0

40

60

80

100

20

ALV1000

81 83 8177

58

ALV600RBV

ALV800RBV

ALV600Peg

P/R0

40

60

80

100

20

ALV1000

8293 91

ALV600RBV

ALV800RBV

82 84 93 39 40n = 17 29 32n =


Co-Pilot: 12-Wk ABT-450/r + ABT-333 + RBV in Tx-Naive and -Exp’d GT1 Patients Interim analysis of nonrandomized, prospective, open-label phase II trial


Treatment-naive patients infected with

genotype 1 HCV(n = 33)

ABT-450/Ritonavir 250/100 mg QD + ABT-333 400 mg BID + RBV 1000-1200 mg QD

(n = 19)


(n = 14)

Wk 12


(n = 17)

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


Pat

ien

ts (

%)

0

40

60

80

100

20

ABT-450/r 250/100 mg QD+ ABT-333 + RBVTreatment naive

(n = 19)

ABT-450/r 150/100 mg QD+ ABT-333 + RBVTreatment naive

(n = 14)

ABT-450/r 150/100 mg QD+ ABT-333 + RBV

Nonresponders(n = 17)

RVReRVRSVR4SVR12

90 90 95 95

79 79

93 93

77

5947 47


Co-Pilot: Safety Outcomes

Laboratory Abnormalities of Interest, %

Tx Naive,ABT-450/r 250/100 mg

+ ABT-333 + RBV(n = 19)

Tx Naive, ABT-450/r 150/100 mg

+ ABT-333 + RBV (n = 14)

Tx Experienced,ABT-450/r 150/100 mg

+ ABT-333 + RBV (n = 17)

Total bilirubin ≥ 2 x ULN

15.8 21.40

Creatinine ≥ 1.5 ULN* 10.5 0 0

CrCl < 50 mL/min* 10.5 0 0

ALT ≥ 5 x ULN 5.3 0 0

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


*Creatinine elevations and shortened creatinine clearance occurred in same 2 patients.


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

Gane E, et al. EASL 2012. Abstract 1412.

Tx-naive patients

with chronic

GT1 HCV(N = 169)

Mericitabine 1000 mg BID +Danoprevir/Ritonavir

100/100 mg BID +Ribavirin 1000-1200 mg/day

Follow-up

Wk 12 Wk 24 Wk 36 Wk 48

eRVR2

Mericitabine 1000 mg BID +Danoprevir/Ritonavir

100/100 mg BID +Placebo

Mericitabine + Danoprevir/Ritonavir +

Ribavirin

Mericitabine + Danoprevir/Ritonavir +

Ribavirin

Mericitabine + Danoprevir/Ritonavir

Mericitabine + Danoprevir/Ritonavir

Follow-up

Follow-up

Follow-up

Follow-up

Follow-up

eRVR2

No eRVR2

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

No eRVR2


INFORM-SVR: SVR12 Rates According to HCV Subtype and IL28B Genotype SVR12 rates higher for GT1b, IL28B non-CC patients

Gane E, et al. EASL 2012. Abstract 1412.

SV

R12

(%

)

0

40

60

80

100

20

Overall CC Non-CC

IL28B Genotype

n/N =

41

26

71

3227

5044

25

76

All (n = 64)GT1a (n = 43)GT1b (n = 21)

26/64 11/43 15/21 6/19 4/15 2/4 20/45 7/28 13/170

40

60

80

100

20

n/N =

SVR12 Rates in Patients Receiving 24 Wks MCB + DNV/r + RBV


Daclatasvir + GS-7977

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

Sulkowski M, et al. EASL 2012. Abstract 1422.

Treatment-naive patients with

GT2 or 3 HCV infection

(n = 44)

Daclatasvir + GS-7977(n = 14)

Daclatasvir + GS-7977(n = 14)

Follow-up

Daclatasvir + GS-7977 + Ribavirin(n = 14)

Daclatasvir + GS-7977 + Ribavirin(n = 15)

Wk 1 Wk 24 Wk 48

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.

Treatment-naive patients with GT1a or 1b

HCV infection(n = 44)

Follow-up

GS-7977 (n = 15)

Daclatasvir + GS-7977GS-7977 (n = 16)

Follow-up

Follow-up

Follow-up

Follow-upA

B

C

D

E

F



Pat

ien

ts (

%)

0

40

60

80

100

20

100 100 100

87 8693

100100 100

Genotype 1a/1b HCV

n =

Group AGroup BGroup C

Light:< LODDark: < LLOQ anddetectable

8793

73

87 8693

100 100 100

15 14 15 15 14 15 15 14 15

Wk 4 Wk 24 (EOT)

SVR4

mITT analysis, bars not reaching 100% after Wk 4 reflect missing values.

0

40

60

80

100

20

100100 10094

100

86

100

86†

Genotype 2/3 HCV

n =

Group DGroup EGroup F

Light:< LODDark: < LLOQ anddetectable

8879

64

93 9386 88

100

79

16 14 14 16 14 14 16 14 14

Wk 4 Wk 24 (EOT)

SVR4

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).

Pat

ien

ts (

%)

88*

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


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


Tx-naive patients with GT1

HCV (7% to 17% in each group had

cirrhosis)(N = 362)

BI 201335 120 mg QD + BI 207127 600 mg TID + RBV

(n = 81)


(n = 80)


(n = 77)

Wk 16

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)*

Stratified by HCV subtype and IL28B genotype

*Randomization to this arm stopped early due to FDA concerns regarding lack of RBV.

12-wk follow-upfor SVR12

Wk 28 Wk 40

Weight-based RBV dosing (1000-1200 mg/day).


68

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


SV

R12

(%

)

0

40

60

80

100

20

BID28 wks

RBV

TID28 wks

TID40 wks

RBV

TID28 wks

RBV

TID16 wks

RBV

32

71

38

71

42

62

32

82

53

0

1a non-CC All 1b and 1a-CC

SVR According to IL28B and HCV Subtype (ITT)

59

All patients

6156

39


SOUND-C2: With BID Dosing, Higher SVR12 in Pts With GT1b or GT1a-IL28B CC


SV

R12

(%

)

n/N =

32

7584 82

1anon-CC

1aCC

1bnon-CC

1bCC

SVR According to IL28B and HCV Subtype:BID 28 Wks + RBV (ITT)

0

40

60

80

100

20

7/22 6/8 31/37 9/11

HCV Subtype and IL28B Genotype


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

Favorable safety with BID dosing, higher rates of discontinuation and serious AEs with TID dosing

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

Soriano V, et al. EASL 2012. Abstract 1420.

TID 16, 28, 40 wks*

RBV

SV

R (

%)

0

40

60

80

100

20

BID 28 wks

RBV

TID 28 wks

*SVR12 data not yet available for TID 40 wk arm, so SVR4 rates used in analysis.

43

3/7 9/14 2/6 5/7 0/0 1/3

64

33

71

33

GT1aGT1b

SVR12 According to HCV GT

n/N =


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 + weight-based RBV 1000-1200 mg/day for 12 wks

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

– 1 late relapse at posttreatment Wk 36; resistance variant observed only in polymerase

– Y448H variant observed in 99% of clones sequenced

Lawitz E, et al. EASL 2012. Abstract 13.

RVR eRVR SVR12 SVR24

Pat

ien

ts (

%)

0

40

60

80

100

20

100 100

91 91


4-Drug Therapy With GS-5885, GS-9451, Tegobuvir, and RBV in Tx-Naive GT1 HCV Interim analysis of randomized phase II study


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)

Randomized 1:2; stratified by HCV RNA

(≤ vs > 800,000 IU/mL) and HCV 1 subtype (1a vs 1b)

*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.


Ribavirin (n = 94)

Wk 2* Wk 12 Wk 24


Ribavirin

Follow-up

Rerandomized†

Follow-upfor SVR24


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



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

Among pts with virologic breakthrough (7.0%) or relapse (9.3%), almost all had trough daclatasvir and asunaprevir plasma concentrations below median

Suzuki F, et al. EASL 2012. Abstract 14.

Wk 4RVR

Wk 12cEVR

End ofTreatment*

SVR12

HC

V R

NA

Un

de

tec

tab

le (

%)

0

40

60

80

100

20

*End of treatment = Wk 24 or last on-treatment visit for pts who discontinued early.ITT (missing = failure) analysis.

SVR24

Null responders (n = 21)

Ineligible/intolerant (n = 22)

52

86 91 91 91 91 91

6464

86

11/21

19/22

19/21

20/22

19/21

19/21

19/21

14/22

14/22

19/22

ASV and DCV Trough Plasma Concentrationsin Patients With SVR or Virologic Failure

800

600

400

200

100

100 200 400 600 800 1000

Daclatasvir Ctrough (ng/mL)

As

un

ap

rev

ir C

tro

ug

h (

ng

/mL

)Virologic failures

SVRRelapseBreakthrough

Note: Multiple determinationare shown for some patients.*Pharmacokinetic values from asingle patient with documentednoncompliance after sampling.

*

*

Median 57M

ed

ian

20

1

n/N =


*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: Danoprevir/r + PegIFN/RBV in GT1/4 Treatment-Naive Patients Interim analysis of multicenter, randomized, open-label phase IIb study

Everson G, et al. EASL 2012. Abstract 1177.

Treatment-naive pts with GT1/4

HCV infection, F0-2 fibrosis, HCV RNA

≥ 50,000 IU/mL(N = 421)

Danoprevir/Ritonavir 200/100 mg q12h + P/R

(n = 94)


(n = 93)


(n = 94)

Wk 12 Wk 24 Wk 36

Danoprevir/r 100/100 mg q12h

+ P/R*(n = 94)

P/R (rollover offered to patients without cEVR)

DNV/r 100/100 mg q12h + P/R

Follow-upfor SVR24

Wk 48 Wk 60

DNV/r 200/100 mg q12h + P/R P/RRollover

==


DAUPHINE: Preliminary SVR12 Rates in Pts Treated for 24 Wks With DNV/r + P/R SVR12 rates increased with higher doses of DNV/r

Everson G, et al. EASL 2012. Abstract 1177.

SV

R12

(IT

T),

(%

)

0

40

60

80

100

20

86

77

65

DNV/r 200 mg + P/RDNV/r 100 mg + P/RDNV/r 50 mg + P/R

79/92 72/93 61/94n/N =


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

Llovet J, et al. EASL 2012. Abstract 1398.

Mos

Pro

ba

bil

ity

Ali

ve

0

0.4

0.6

0.8

1.0

0.2

Overall Survival

Brivanib Placebo183/263

9.4101/132

8.20.89 (0.69-1.15)

.3307

Events/patients, nMedian OS, mosHR (95.8% CI)*P (stratified log rank)

Pts at Risk, nBrivanibPlacebo

*95.8% CI adjusted for interim analysis

0

263132

2

239117

4

20894

6

16375

8

13464

10

9549

12

7735

14

5525

16

4019

18

3016

20

1711

22

127

24

54

26

23

28

02

30

00

Time to Progression

Mos

Pro

ba

bil

ity

of

Pro

gre

ss

ion

0

0.4

0.6

1.0

0.8

0.2

Brivanib Placebo151/263

4.275/132

2.70.56 (0.42-0.78)

.0001

Events/patients, nMedian TTP, mosHR (95% CI)P (log rank)

Pts at Risk, n BrivanibPlacebo

0

263132

2

14445

4

9221

6

376

8

205

10

92

12

31

14

21

16

11

18

01

22

01

24

00

20

01


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