April 11-15, 2007 Barcelona, Spain *CCO is an independent medical education company that provides...

April 11-15, 2007

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

of the 2007 Annual Meeting of the European Association for the Study of the Liver*

Clinical Updates in HCV TreatmentCCO Independent Conference Coverage

clinicaloptions.com/hep

EASL 2007: Clinical Updates in HCV Treatment

About These Slides

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Users are encouraged to include these slides in their own 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These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.

We are grateful to Ira M. Jacobson, MD, with the Weill Medical College of Cornell University in New York, New York, for aiding in the content development of these slides.

Novel Protease Inhibitors for Hepatitis C



Telaprevir 750 mg every 8 hrs + Peg-IFN alfa-2a + RBV

(n = 80)

Peg-IFN alfa-2a + RBV(n = 80)

Peg-IFN alfa-2a + RBV(n = 80)

Telaprevir 750 mg every 8 hrs + Peg-IFN alfa-2a + RBV

(n = 80)Telaprevir 750 mg every 8 hrs

+ Peg-IFN alfa-2a + RBV(n = 20)

Peg-IFN alfa-2a + RBV (n = 80)

McHutchison JG, et al. EASL 2007. Late Breaker 786.

Randomized, phase II trial

(N = 260planned)

Week 12: Interim Analysis

*

*Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. †Patients must achieve undetectable HCV RNA at Week 4 (< 10 IU/mL) and at last test before stopping therapy at 12 or 24 weeks.

Week 24 Week 48

†

Week 72

24-Week

Follow-up

PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients Current analysis: data on all patients through Week 12 of treatment

– Also patients in 12-week treatment arm who made it to Week 20 of follow-up

† 24-Week

Follow-up

24-Week

Follow-up

24-Week

Follow-up

Placebo + Peg-IFN alfa-2a + RBV

(n = 80)



PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients High rates of RVR (Week 4)

and EVR (Week 12)

Virologic breakthrough rates– Telaprevir: 7% (12/175)

– Controls: 3% (2/80)

Follow-up for 12-week treatment arm– 67% (6/9) patients who

achieved Week 4 RVR and discontinued treatment after 12 weeks were HCV RNA negative 20 weeks posttreatment


P < .001

Virologic Response Rates(HCV RNA < 10 IU/mL)

79

11

Week 4

Pat

ien

ts (

%)

0

20

40

60

80

100

70

39

Week 12

Telaprevir + peg-IFN + RBV (pooled; n = 175 dosed)

Peg-IFN + RBV (n = 75 dosed)

P < .001



PROVE 1: Telaprevir + Peg-IFN/RBV in Treatment-Naive HCV GT 1 Patients Discontinuation due to adverse events through Week 12

– Control arm: n = 2 (3%) – Telaprevir: n = 19 (11%) – Rash most common cause for telaprevir discontinuation (n = 7)

– Median time to onset of severe rash: 62 days


Adverse Event, % Telaprevir + Peg-IFN + RBV(Pooled; n = 175)

Peg-IFN + RBV(n = 75)

Severe rash 6 0

Nausea 50 30

Severe 2 2

Pruritus 37 20

Diarrhea 34 21

Grade 1 anemia 40 29

Grade 2 anemia 17 9

Novel Polymerase Inhibitors for Hepatitis C



Valopicitabine in Treatment-Naive HCV Genotype 1 Patients

Lawitz E, et al. EASL 2007. Abstract 14.

Treatment-naive

patients with HCV GT 1

(N = 172*)

Week 12-22Study Amendment*

Week 1 Week 4

Peg-IFN alfa-2a

alone

Week 48

Peg-IFN alfa-2a 180 µg/week +Valopicitabine 800 mg/day

(n = 34)No TX

Valopicitabine200 mg/day


(n = 34)Valopicitabine

ramped from400-800 mg/day


(n = 34)

Valopicitabine800 mg/day


(n = 36)

Peg-IFN alfa-2a 180 µg/week + Valopicitabine 800 mg/day(n = 35)

24-Week

Follow-up

*Week 12 GI-related adverse events resulted in reduction of valopicitabine dose in arms receiving 800 mg; these patients were randomly reassigned 1:1 to valopicitabine 200 mg or 400 mg + peg-IFN for the remainder.

Week 72



Valopicitabine in Treatment-Naive HCV Genotype 1 Patients (cont’d) 800-mg groups pooled for efficacy analysis Mean HCV RNA decrease at Week 48

– Valopicitabine 200 mg + peg-IFN alfa-2a: -4.02 IU/mL– Valopicitabine 800 mg + peg-IFN alfa-2: -3.94 IU/mL


Valopicitabine 200 mg + peg-IFN alfa-2a (n = 34)

Valopicitabine 800 mg + peg-IFN alfa-2a (n = 139)

44

625350 47

38

0

20

40

60

80

100

Week 12 Week 24 Week 48

Pat

ien

ts (

%)

Proportion of Patients With Undetectable HCV RNA (< 20 IU/mL)*

*Dropout = treatment failure.



Valopicitabine in Treatment-Naive HCV Genotype 1 Patients (cont’d) Discontinuation rates, adverse events tended to be higher with 800-mg dose

– 7 treatment-related serious adverse events Incidence of valopicitabine-related GI adverse events dose dependent


Outcome, % Valopicitabine 200 mg + Peg-IFN alfa-2a (n = 34)

Valopicitabine 800 mg + Peg-IFN alfa-2a (n = 139)

Treatment discontinuation 38 55

Diarrhea 38 44

Nausea 65 81

Vomiting 38 53

Headache 27 30

Fatigue 44 50

Depression 21 23

Flu-like symptoms 18 29



Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBV Phase IIb study of valopicitabine ± peginterferon

Afdhal NH, et al. EASL 2007. Abstract 6.

Week 1 Week 48 Week 72

*Data pooled from two 800-mg groups in current analysis.

GT 1 previous nonresponders with

HCV RNA ≥ 105 IU/mL, ALT < 5 x ULN, and compensated liver

disease

(N = 190)

Valopicitabine 800 mg/day monotherapy

Val400 mg/day Peg-IFN + Valopicitabine 400 mg/day

Val 400 →800 mg/day

Val800 mg/day

Follow-up

No Treatment Peg-IFN + RBV 1000-1200 mg

Peg-IFN + Valopicitabine 800 mg*

Peg-IFN + Valopicitabine 800 mg*

(n = 21)

(n = 42)

(n = 42)

(n = 42)

(n = 43)



Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBV


Week 48 Mean Reduction in HCV RNA Virologic Response Rates (< 50 IU/mL)

15

3

20

0

24

00

20

40

60

80

100

Week 48 SVR

Pat

ien

ts (

%)

Valopicitabine 400 mg/day + Peg-IFN

Peg-IFN + RBV Valopicitabine 800 mg/day + Peg-IFN (pooled data)

Mea

n lo

g10

Ch

ang

e

-2.29 -2.23

-3.11-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0



Retreatment With Valopicitabine in HCV Nonresponders to Peg-IFN/RBVOutcome, % Valopicitabine

800 mg/day + Peg-IFN(n = 82)

Valopicitabine 400 mg/day +

Peg-IFN(n = 41)

Peg-IFN +RBV

(n = 34)

Discontinued treatment 78 88 85 Due to adverse event 23 20 3

Nausea 82 73 35

Fatigue 56 51 68

Vomiting 66 49 9

Diarrhea 49 32 15

Headache 39 42 27

Depression 28 10 29

Insomnia 27 10 29

Neutropenia 24 29 12




HCV-796 + Peg-IFN in Treatment-Naive Hepatitis C Patients

Villano SA, et al. EASL 2007. Abstract 50.

Treatment-naive chronic hepatitis C patients without advanced or decompensated liver

disease

(N = 65)

HCV-796 100 mg BID + Peginterferon alfa-2b 1.5 µg/kg

(n = 12)

Day 14:End of Treatment

Day 1:Peg-IFN Dose 1

Day 7:Peg-IFN Dose 2


(n = 10)


(n = 12)

Placebo +Peginterferon alfa-2b 1.5 µg/kg

(n = 19)


(n = 12)

Day 28Follow-up



HCV-796 in Treatment-Naive Hepatitis C Patients


*< 50 IU/mL.

Peg-IFN (n = 15)

100 mg HCV-796+ Peg-IFN (n = 10)

250 mg HCV-796+ Peg-IFN (n = 9)

1000 mg HCV-796+ Peg-IFN (n = 12)

500 mg HCV-796+ Peg-IFN (n = 10)

Day 14 Change in HCV RNA From Baseline

≥ 2 Log Change ≥ 3 Log Change HCV RNA Negative*

40

787070

92

0

20

40

60

80

100

Pat

ien

ts (

%)

13

67 7070 67

13

33 3020

33



HCV-796 in Treatment-Naive Hepatitis C Patients (cont’d)


Mea

n l

og

10 C

han

ge:

Day

14

Genotype 1 Genotype Non-1

Peg-IFN

100 mg H

CV-796 + P

eg-IFN

250 mg H

CV-796 +

Peg-IF

N

500 m

g HCV-7

96 + P

eg-IF

N

1000 m

g HCV-7

96 +Peg-IF

N

-4

-3

-2

-1

0

1

-5

Peg-IFN

100 mg H

CV-796 + P

eg-IFN

250 mg H

CV-796 +

Peg-IF

N

500 m

g HCV-7

96 + P

eg-IF

N

1000 m

g HCV-7

96 + P

eg-IF

N

Novel Small Molecule Therapies for Hepatitis C



Efficacy of DEBIO-025 in HIV/HCV-Coinfected Patients DEBIO-025: oral small

molecule inhibitor of cyclophilin

1200 mg twice daily for 14 days (n = 16) vs placebo (n = 3) in treatment-naive HIV/HCV-coinfected patients

Biphasic viral decay kinetics demonstrated

Effective across GT 1, 3, 4

No rebounds noted

Herrmann E, et al. EASL 2007. Abstract 88.

1

2

3

4

5

6

7

8

9

-28 0 10 20 30 40 50Time (Days)

DEBIO-025 Placebo

HC

V R

NA

(lo

g1

0 c

op

ies/

mL

)

Treatment

Figure used with permission from Dr. Eva Herrmann.



NS4A Antagonist ACH-806 in HCV Genotype 1–Infected Patients ACH-806 300 mg twice daily for 5 days (n = 8) vs placebo (n = 2) in naive or

experienced patients

Pottage JC, et al. EASL 2007. Abstract 783.

Figure used with permission from John C. Pottage, Jr., MD.

ACH-806 (n = 8) Placebo (n = 2)

0.2

0

-0.2

-0.4

-0.6

-0.8

-1.0

Mea

n C

han

ge

in H

CV

R

NA

log

10 (

IU/m

L)

2 4 6 8 10 12 14 16 18Study Day

0 20

Treatment



NS4A Antagonist ACH-806 in HCV Genotype 1–Infected Patients (cont’d) 4 patients had > 1 log10 IU/mL reduction in HCV RNA

– Mean reduction: 0.91 log10 IU/mL

6 individuals had increases in serum creatinine

– Mean Day 3 increase: 0.43 mg/dL

– Mean Day 5 increase: 0.49 mg/dL

Drug development halted due to renal toxicity

Proof of concept demonstrated

Pottage JC, et al. EASL 2007. Abstract 783.

Novel Interferons for Hepatitis C



Albinterferon Alfa-2b/RBV Treatment in Genotype 2/3 Patients Interim analysis of multicenter, randomized, open-label, phase II trial

– Albinterferon alfa-2b recombinant interferon fused with human serum albumin

Treatment-naive patients chronically infected with HCV

genotype 2/3

(N = 43)

Albinterferon alfa-2b 1500 µg every 2 weeks subcutaneously +

Ribavirin 800 mg/day(n = 21)

Albinterferon alfa-2b 1500 µg every 4 weeks subcutaneously +

Ribavirin 800 mg/day(n = 22)

Week 24Stratification by

HCV genotype (2 or 3) andHCV RNA (< vs ≥ 800,000 IU/mL)

Follow-up planned for 24 additional weeks; interim follow-up performed at Week 36

Bain VG, et al. EASL 2007. Abstract 9.



Albinterferon Alfa-2b/RBV Treatment in Genotype 2/3 Patients (cont’d)

Bain VG, et al. EASL 2007. Abstract 9.

Alb-IFN Q2W + RBV (n = 21) Alb-IFN Q4W + RBV (n = 22)

76.285.7 85.7

66.768.2

95.5 95.5

72.7

0

20

40

60

80

100

Week 4* Week 12* Week 24†

(EOT)Week 36†

(Post-Tx)

Un

det

ecta

ble

HC

V R

NA

(%

)

Week 36 OutcomesAccording to Genotype

*Limit of detection, 43 IU/mL.†Limit of detection, 10 IU/mL.

GT 2† GT 3†

Virologic Outcomes

80.0

54.560.0

83.3

0

20

40

60

80

100

Un

det

ecta

ble

HC

V R

NA

(%

)

Figures used with permission from Vincent G. Bain, MD, FRCP(C).



Albinterferon-Based Therapy vs Standard of Care

Zeuzem S, et al. EASL 2007. Abstract 779.

Interferon-naive, genotype 1,

chronic hepatitis C patients

(N = 458)

Albinterferon alfa-2b 900 µg Q2W +Weight-Based Ribavirin 1000-1200 mg/day

(n = 118)


(n = 110)

Week 48

Stratification by HCV RNA (< vs ≥ 800,000 copies/mL) and

body mass index (< vs ≥ 25)


(n = 116)

Peginterferon alfa-2a 180 µg/week +Weight-Based Ribavirin 1000-1200 mg/day

(n = 114)

Week 72

24-Week

Follow-up

Week 60:Current Interim

Analysis



Albinterferon-Based Therapy vs Standard of Care (cont’d)

Figure used with permission from Stefan Zeuzem, MD.

25

70 73

59

34

75 80

56

18

53

70

53

26

66

78

54

0

20

40

60

80

100

Week 4* Week 12* End ofTreatment†

Week 12Posttreatment†

Pat

ien

ts (

%)

Alb-IFN 900 μg Q2W

Alb-IFN 1200 μg Q2W

Alb-IFN 1200 μg Q4W

Peg-IFN 180 µg/week

*< 43 IU/mL.†< 10 IU/mL.

Proportion of Patients With Undetectable HCV RNA




Albinterferon-Based Therapy vs Standard of Care (cont’d) Quality of life significantly less impaired for patients on

albinterferon 1200 µg every 4 weeks vs those on peginterferon at Weeks 12, 24, and 48 (P < .05)


Safety and Dose Reductions, %

Alb-IFN 900 µg Q2W + RBV

(n = 118)


(n = 110)


(n = 116)

Peg-IFN 180 µg Q1W + RBV

(n = 114)

Severe adverse events 31.4 40.9 29.3 27.2

Treatment discontinuation due to adverse event

9.3 19.1 12.1 6.1

Interferon dose reduction 29.7 33.6 10.3 28.1

Due to adverse event 4.2 7.3 3.4 8.8

Due to lab abnormality 25.4 27.3 6.0 22.8



Recombinant IFN Omega for Treatment-Naive GT 1 Patients Randomized, open-label, phase II trial

Novozhenov V, et al. EASL 2007. Abstract 11.

Treatment-naive patients with genotype 1

chronic HCV infection

(N = 102)

Interferon Omega 25 µg/day (n = 35)

Interferon Omega 25 µg/day +Ribavirin 1000/1200 mg BID

(n = 67)

Week 48:ETR

Week 12:Subjects must demonstrate

a > 2 log10 reduction in HCV RNA level* to continue

Week 72:SVR

*Limit of detection < 600 IU/mL.

Follow-up



Recombinant IFN Omega for Treatment-Naive GT 1 Patients (cont’d)

Novozhenov V, et al. EASL 2007. Abstract 11.

6054

17

8478

36

0

25

50

75

100

EVR HCV RNA- Week 12 ETR

Pat

ien

ts (

%)

Virologic Response Rates

6

36

SVR

P = .014

P = .001

Omega alone (n = 35) Omega + ribavirin (n = 67)

Ribavirin Analogues for Hepatitis C



VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C Multicenter, active-control, parallel group, double-blind

phase III study

Marcellin P, et al. EASL 2007. Abstract 10.

2:1 Randomization

Taribavirin 600 mg BID +Peginterferon alfa

(n = 644)

Ribavirin 1000/1200 mg BID +Peginterferon alfa

(n = 318)

24 or 48 Weeks of Treatment*

24 Weeks of Follow-up

Treatment-naive chronic hepatitis C patients

(N = 962)

*According to genotype.



VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C (cont’d)


SVR Rate*, % Ribavirin + Peginterferon

(n = 318)

Taribavirin + Peginterferon

(n = 644)

Overall 55 40

Genotype 1 patients 44 27

Genotype 2/3 patients 81 67

*HCV RNA < 39 IU/mL.




Higher rate of anemia in ribavirin vs taribavirin group

– 22% vs 6%, respectively (P < .001)

Post hoc subgroup analysis: higher SVR rates in those receiving > 15 mg/kg taribavirin

– Increase in anemia rate in those receiving > 15 mg/kg of taribavirin

RibavirinTaribavirin Dose, mg/kg

≤ 13 > 13-15 > 15-18 > 18

Patients, n 318 171 164 190 119

SVR, % 55 26 42 47 48

Anemia, % 22 4 2 8 13

VISER 2: Efficacy of Taribavirin vs Ribavirin in Hepatitis C (cont’d)

Using Virologic Response to Determine Treatment Duration



Treatment length

determined

Treatment-naive patients with

HCV GT 1 infection

(N = 694)

Peg-IFN + RBV for 48 weeks (n = 235)


Peg-IFN + RBVfor 24 weeks

(n = 122)


Week 24 Week 48 Week 72 Week 96

Follow-up

Mangia A, et al. EASL 2007. Abstract 7.

Extended Treatment in Genotype 1 Slow Responder Patients

Standard Tx regardless of

response

HCV RNA negative at

Week 4

HCV RNA negative at

Week 8

HCV RNA positive at

Week 8

Week 8

Follow-up

Follow-up

Follow-up



Mangia A, et al. EASL 2007. Abstract 7.

Extended Treatment in Genotype 1 Slow Responder Patients (cont’d)

Virologic Outcomes in Week 12 Responders (< 50 IU/mL)

72-week treatment

Pat

ien

ts (

%)

0

20

40

60

80

100

End of Treatment Response

7768

SVR

37

63

P = .06

48-week treatment

Predictors of SVR



Week 4 Ribavirin Concentration as a Predictor of SVR Week 4 ribavirin concentrations correlated with SVR in 22 patients

– Cutoff of 2 mg/L significantly associated with SVR

Maynard M, et al. EASL 2007. Abstract 619.

SV

R R

ate*

(%

)

Week 4 Ribavirin (mg/L)

< 1.51 1.51-1.73 1.74-2.43 > 2.43

Week 4 Ribavirin (mg/L)

20

6 50

20

40

60

80

100

33

50

6

80

5

SV

R R

ate*

(%

)

≤ 2 > 2

27

1570

20

40

60

80

10086

P = .05P = .03

n = n =

*Measured through quantitative PCR.



Relationship Between Renal Function and SVR in Hepatitis C Patients German multicenter, open-label, observational study

Treatment-naive HCV patients (N = 10,326) screened

– Initiated peginterferon plus ribavirin with complete GFR data sets (n = 1615)

– Patients stratified into 2 groups

– Normal GFR: > 90 mL/min/1.73 m2 (n = 1498)

– Low GFR: 60-90 mL/min/1.73 m2 (n = 107)

– 10 patients with GFR < 60 mL/min/1.73 m2 excluded from analysis

GFR differed according to sex, age, and HCV genotype but not according to weight or BMI

Zehnter E, et al. EASL 2007. Abstract 656.



Relationship Between Renal Function and SVR in Hepatitis C Patients (cont’d) GFR affected response rates in genotype 1,4 but not genotype 2,3 patients Anemia more common among patients with low GFR

Zehnter E, et al. EASL 2007. Abstract 656.

Normal GFR (> 90; n = 1498) Low GFR (> 60-90; n = 107)

Pat

ien

ts (

%)

16.1

35.5

0

20

40

60

80

100 Anemia

Pat

ien

ts (

%)

n = 38

49.7

76.0

61.4

33.3

75.0

41.1

0

20

40

60

80

100

Genotype 1/4 Genotype 2/3Total

Sustained Virologic Response

413 29 507 15920 44n = 241

Figures used with permission from Elmar Zehnter, MD.

Total

Summary and Conclusions



Conclusions

Protease inhibitors

High rates of rapid response with telaprevir plus peginterferon/ribavirin in naive patients based on interim data

– High sustained response rates in those undergoing 12 weeks of therapy following Week 4 RVR

– Treatment-limiting adverse effects include rash, GI problems

Polymerase inhibitors

Valopicitabine 200 mg/day plus peginterferon alfa-2a resulted in end of treatment response in one half of treatment-naive genotype 1 patients

Poor SVR rates with valopicitabine/peginterferon retreatment

– May be due to high discontinuation rates, lack of ribavirin use



Conclusions (cont’d)

Polymerase inhibitors (cont’d)

Viral suppression in ~ one third of treatment-naive patients receiving HCV-796/peginterferon alfa-2b

Small molecule therapies

Novel NS4A antagonist ACH-806 displayed strong viral suppression

– Drug halted due to renal toxicity

DEBIO-025 effective across genotypes in 14-day treatment trial




Novel interferons in interferon-naive patients

Week 12 posttreatment sustained response rates comparable to standard of care with albinterferon every-4-week dosing

– Significantly better quality of life

High Week 12 posttreatment sustained response rates with albinterferon in genotype 2/3 patients

– Best rates in genotype 3 individuals

36% SVR rate with interferon omega plus ribavirin in genotype 1 patients




Ribavirin analogues Taribavirin associated with significantly lower SVR rates than

ribavirin, except at higher doses

Determining optimal treatment duration Extending treatment to Week 72 in slow responders improved

SVR rates vs 48 weeks of treatment

Predictors of SVR Week 4 serum ribavirin concentration > 2 mg/L associated with

higher SVR rates

Poor renal function associated with lower SVR rates in genotype 1/4 patients

Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications

Expert Highlights: download mp3 files and listen to our experts review the highlights of this conference

Expert Recap (slides and audio) plus downloadable PowerPoint slides

clinicaloptions.com/barcelona2007

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