hcv highlights from aasld 2012 - chronic liver disease foundation

Boceprevir (BOC) Combined with Peginterferon alfa-

2b/Ribavirin (P/RBV) in Treatment-Naïve Chronic HCV

Genotype 1 Patients with Compensated Cirrhosis: Sustained

Virologic Response (SVR) and Safety Subanalyses from the

Anemia Management Study

Lawitz E, Zeuzem S, Nyberg LM, Nelson DR, Rossaro L,

Balart LA, K. Reddy R, Morgan T, Deng W, Koury KJ,

Alves K, Dutko F, Wahl J, Pedicone L, Poordad F

Abstract 50, AASLD 2012

HCV Highlights from AASLD 2012

November 9 - 13, 2012 Boston, MA

Boceprevir/PegIFN/ RBV in Treatment-Naïve Chronic

HCV Genotype 1 Patients with Compensated Cirrhosis:

Anemia Management

Objective

• To evaluate SVR rates and tolerability of two

anemia management strategies (RBV dose

reduction [DR] or erythropoietin [EPO] use) in

cirrhotics vs. non-cirrhotics treated with

BOC/PegIFN/RBV

Lawitz E et al. Hepatology 2012; 56(Suppl S1):216A



Anemia Management


After 4-week lead-in

with P/RBV, all

patients initiated

boceprevir.

Hb at wk 0, 2, 4, 6,

8, 10, 12, 24,

28, 34, 40, 48.

Randomized if

Hb ~10 g/dl

EPO

(n=251)

RBV DR

(n=249)

If Hb≤8.5 g/dL,

secondary

intervention

(RBV DR arm

could use EPO;

EPO arm could

use RBV DR)

If Hb>10 g/dL, patients

treated but not randomized

(n=187)

Study Design



Anemia Management


Initial dosing • PegIFN α-2b administered subcutaneously at 1.5 g/kg

once weekly, plus RBV using weight-based dosing of

600-1400 mg/day in a divided daily dose

Interventions for anemia • RBV DR by increments of 200 mg at the discretion of the

investigator (first increment of 400 mg if initial dose was

1,400 mg/day)

• EPO was started at 40,000 units/wk and could be

modified at the investigator’s discretion to doses of

20,000 to 60,000 units/wk

• If Hb≤7.5 g/dL, all study drugs were discontinued



Anemia Management


10%

71%

82%

10%

71%

82%

0

20

40

60

80

100

EOT SVR Relapse

% of Patients

RBV DR

EPO

Primary Efficacy Results

203/

249

205/

251

178/

249

178/

251 19/ 196

19/ 197



Anemia Management


18%

55%

68%

11%

64%

76%

0

20

40

60

80

100

EOT SVR Relapse

% of Patients

Cirrhotics

Non-Cirrhotics

Efficacy Results: Cirrhotics and Non-Cirrhotics

41/

60

460/

604

33/

60

387/

604 7/ 40

47/ 433



Anemia Management


73%

57%

72%64%

0

20

40

60

80

100

Cirrhotics Non-Cirrhotics

% of Patients

SVRs Were Similar with RBV Dose Reduction

or EPO

13/

23

16/

25

162/

221

157/

217

RBV DR RBV DR EPO EPO



Anemia Management

Category

Number (%) of Patients

Cirrhotics

(N=60)

Non-cirrhotics

(N=604)*

Treatment-emergent AEs 60 (100) 597 (99)

Serious AEs 12 (20) 72 (12)

Death 0 (0) 1 (<1)ǂ

Life-threatening treatment-

emergent AEs

2 (3) 13 (2)

Study drug discontinuation due

to AE

10 (17) 94 (16)

*Includes all treated patients (RBV DR, EPO, treated and not randomized) Excludes 23 patients with inadequate portal tracts/missing for cirrhosis

ǂEvent assessed by investigator as unlikely related to study medication


Summary of Adverse Events



Anemia Management

Hematologic Variables Cirrhotics

n/m* (%)

Non-cirrhotics

n/m (%)

Hemoglobin concentration

6.5 g/dL to 8.0 g/dL

<6.5 g/dL

4/59 (7)

0/59 (0)

31/601 (5)

0/601 (0)

Neutrophil counts

500 to <750/mm3

<500/mm3

14/59 (24)

12/59 (20)

160/601 (27)

72/601 (12)

Platelet counts

25,000 to <50,000/mm3

<25,000/mm3

13/59 (22)

1/59 (2)

12/601 (2)

1/601 (<1)

Packed red blood cell transfusion 2/60 (3) 14/604 (2)

*n/m = number of patients with characteristic / subtotal


Hematologic parameters



Anemia Management


Conclusions

• SVRs are comparable in cirrhotic patients when

anemia is managed by RBV dose reduction or

EPO

• Rates of anemia and transfusions similar in

cirrhotics and non-cirrhotics; higher rates of

neutropenia and thrombocytopenia in cirrhotics

• Ribavirin dose reduction should be considered

as the initial management strategy for anemia

Safety and Efficacy of Telaprevir or Boceprevir in Combination with

Peginterferon alfa/Ribavirin, in 455 Cirrhotic Non Responders.

Week 16 Analysis of the French Early Access Program

(ANRS CO20-CUPIC) in Real-Life Setting

Hezode C, Dorival C, Zoulim F, Larrey DG, Pol S, Cacoub P, Canva V, Poynard T,

Samuel D, Bourliere M, Alric L, Raabe J-J, Zarski J-PH, Riachi G, Bernard P-H,

de Ledinghen V, Loustaud-Ratti V, Metivier S, Causse X, Marcellin P, Barthe Y,

Fontaine H, Carrat F, Bronowicki J-P




Safety and Efficacy of Telaprevir or Boceprevir in

Combination with PegIFN/RBV in Cirrhotic Non

Responder Chronic Hepatitis C Patients

Objective

• Week 16 analysis of safety and efficacy of

telaprevir (TVR) or boceprevir (BOC) in

combination with PegIFN/RBV in cirrhotic non

responder hepatitis C patients in a real-life

setting

Hezode C et al. Hepatology 2012; 56(Suppl S1):217A




Methods

• Study involved treatment experienced (relapse, partial

response) HCV patients enrolled in a French Early

Access Program

• 674 genotype 1 patients with compensated cirrhosis

(Child A) were prospectively included

• Received 12W TVR/PegIFN-2a/RBV + 36W

PegIFN/RBV or 4W PegIFN-2b/RBV + 44W

BOC/PegIFN/RBV

• Present analysis limited to 497 patients reaching W16 of

therapy






92%93%92%

58%

77%

64%

42%

3%

0

20

40

60

80

100

Week 4 Week 8 Week 12 Week 16

Patients with undetectable

HCV RNA (%)

Week 16 efficacy data (per protocol analysis) TVR/PegIFN/RBV BOC/PegIFN/RBV

161/ 276

236/ 257

230/ 247

196/ 212

5/ 194

77/ 181

112/ 174

118/ 154




*SCAR: Severe cutaneous adverse reaction


Week 16 safety findings

Patients, n (% patients with at least one event) Telaprevir

n=292

Boceprevir

(n=205)

Serious adverse events (SAEs) 132 (45.2%) 67 (32.7%)

Premature discontinuation

Due to SAEs

66 (22.6%)

43 (14.7%)

54 (26.3%)

15 (7.3%)

Death 5 (2.6%) 1 (0.5%)

Infection (Grade 3/4) 19 (6.5%) 5 (2.4%)

Hepatic decompensation ( Grade 3/4) 6 (2.0%) 6 (2.9%)

Astnenia (Grade 3/4) 16 (5.5%) 12 (5.8%)

Rash (Grade 3/SCAR*) 14 (4.8%) 0

Renal failure 5 (1.7%) 0





Week 16 safety findings Patients, n (% patients with at least one event) Telaprevir

n=292

Boceprevir

(n=205)

Anemia

Grade 2 (8.0 - 9.0 g/dL)

Grade 3/4 (<8.0 g/dL)

EPO use

Blood transfusion

RBV dose reduction

55 (18.8%)

34 (11.6%)

157 (53.8%)

47 (16.1%)

38 (13.0%)

48 (23.4%)

9 (4.4%)

95 (46.3%)

13 (6.3%)

22 (10.7%)

Neutropenia

Grade 3 (500 - <750/mm3)

Grade 4 (<500/mm3)

G-CSF use

6 (2.0%)

2 (0.7%)

7 (2.4%)

2 (1.0%)

7 (3.4%)

9 (4.4%)

Thrombocytopenia

Grade 3 (20,000 - <50,000/mm3)

Grade 4 (<20,000/mm3)

Thrombopoïetin use

28 (9.6%)

9 (3.1%)

4 (1.4%)

10 (4.9%)

3 (1.5%)

2 (1.0%)




*Death, severe infection and hepatic decompensation, n=32 (6.4%)


Multivariate analysis: Baseline predictors of severe complications*

Predictors OR 95% CI P-value

Platelet count 100,000/mm3 3.11 1.32 - 7.73 0.0098

Serum albumin level <35 g/L 6.33 2.66 - 15.07 <0.0001





Multivariate analysis: Baseline predictors of anemia <8g/dL or blood transfusion (n=71/497, 14.3%)

Predictors OR 95% CI P-value

Gender: Female 2.19 1.11 - 4.33 0.023

No lead-in phase 2.25 1.15 - 4.39 0.018

Age 65 years 3.04 1.54 - 6.02 0.0014

Hemoglobin level

12 g/dL for female

13 g/dL for male

5.30 2.49 - 11.25 <0.0001





Conclusions

• Treatment of compensated cirrhotic patients with TVR or BOC

in combination with PegIFN/RBV resulted in high rates on on-

treatment virologic response

• Treatment was associated with increased rates of SAEs and

more difficult management of anemia compared to phase III

trials

• Cirrhotic patients with platelet count 100,000/mm3 or serum

albumin level <35 g/L should be treated on a case by case

basis due increased risk for severe complications

• Cirrhotic patients without predictors of severe complications

should be treated cautiously and carefully monitored

Telaprevir in Combination with Peginterferon Alfa-

2a/Ribavirin in HCV/HIV Co-infected Patients: SVR24

Final Study Results

Sulkowski MS, Sherman KE, Soriano V, Rockstroh J, Dieterich DT, Girard PM,

Bsharat M, Henshaw J, Rubin RA, Garg V, Adda N




Telaprevir/PegIFN/RBV in HCV/HIV Co-Infected Patients

Primary Objectives

• Safety and tolerability of telaprevir (TVR) in combination

with PegIFN/RBV in HCV/HIV co-infected patients

• Proportion of patients who are HCV RNA undetectable

after 12 weeks of TVR/PegIFN/RBV

Secondary Objectives

• Efficacy of TVR/PegIFN/RBV at post-treatment week 12

(SVR12) and 24 (SVR 24); HCV RNA <LLOQ

• Pharmacokinetics of TVR, PegIFN, RBV, and pre-

specified antiretroviral therapy (ART)

Sulkowski M et al. Hepatology 2012; 56(Suppl S1):219A


TVR=telaprevir; P=pegylated interferon; R=ribavirin; EFV=efavirenz; TDF=tenofovir disoproxil

fumarate; FTC=emtricitabine; ATR/r=ritonavir-boosted atazanavir; 3TC=lamivudine


Part A: No ART

TVR + PR PR

Pbo + PR PR

Part B: ART (EFV/TDF/FTC or ATV/r+TDF+FTC or 3TC)

TVR + PR PR

Pbo + PR PR

T/PR

1:1

PR48

(control)

T/PR

2:1

PR48

(control)

Weeks 0 12 24 36 48 60 72

SVR12

SVR12

SVR12

SVR12

SVR24

SVR24

SVR24

SVR24

Study Design: Randomized, Double-Blind, Placebo Controlled Trial



Methods

• PegIFN α-2a dosed at 180 g/week SC + RBV with TVR

or placebo for 12 weeks

– RBV dosed at 800 mg/day (n=33); 5 patients received weight-

based RBV per country-specific protocol in France and Germany

– TVR dosed at 750 mg q8h with atazanavir and 1125 mg q8h with

efavirenz

• HCV RNA assessed at days 1, 2, and 4; weeks 1, 2, 3,

4, 8, 12, 16, 20, 24, 28, 36, and 48; and post-treatment

follow-up visits

– Roche COBAS TaqMan HCV test v 2.9, LLOQ of 25 IU/mL



Methods (cont)

• Futility rules

– Discontinue TVR if HCV RNA >100 IU/mL at week 4 or 8

– Discontinue all HCV drugs if

• HCV RNA >1000 IU/mL or <2 log10 decrease from baseline at

week 12

• Detectable HCV RNA at week 24 or 36

• Viral breakthrough

– Defined as HCV RNA >100 IU/mL after not detected or a >1 log10

increase from adir

– Stop all HCV drugs


TVR=telaprevir; PegIFN=pegylated interferon; RBV=ribavirin; EFV=efavirenz; TDF=tenofovir disoproxil fumarate; FTC=emtricitabine; ATR/r=ritonavir-boosted atazanavir; 3TC=lamivudine Sulkowski M et al. Hepatology 2012; 56(Suppl S1):219A

Efficacy: SVR24

33%

71%

50%

69%

50%

80%

45%

74%

0

20

40

60

80

100

TVR/PegIFN/RBV PegIFN/RBV

SVR24

(%)

No ART EFV/TDF/FTC ATV/r/TDF/FTC Total

5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22



Virologic Outcome, n/N (%) TVR/PegIFN/RBV PegIFN/RBV

SVR 28/38 (74) 10/22 (45)

No SVR

Stopping rule

Viral relapse post-treatment

LLOQ at EOT

Lost to follow-up

10/38 (26)

2/38 (5)

1/32 (5)

3/38 (8)

4/38 (11)

12/22 (55)

8/22 (36)

2/13 (15)

2/22 (9)

0/222 (0)

HCV Treatment Outcome



Most common adverse events in >15% patients: TVR treatment phase (weeks 1 - 12)

N (%) TVR/PegIFN/RBV N=38

PegIFN/RBV N=22

Fatigue Pruritus Headache Nausea Rash Diarrhea Dizziness Pyrexia Depression Anemia Vomiting Myalgia Chills Insomnia

15 (39) 13 (34) 13 (34) 12 (32) 11 (29) 8 (21) 8 (21) 7 (18) 6 (16) 5 (13) 6 (16) 5 (13) 5 (13) 5 (13)

9 (41) 1 (5)

5 (23) 4 (18) 4 (18) 3 (14) 2 (9) 2 (9) 2 (9)

4 (18) 2 (9)

5 (23) 4 (18) 4 (18)



Events of special interest: Overall treatment phase

Adverse events, n (%) TVR/PegIFN/RBV N=38

PegIFN/RBV N=22

Severe rash 0 (0) 0 (0)

Mild or moderate rash 13 (34) 5 (23)

Any anemia (hemoglobin <10 g/dL) 7 (18) 4 (18)

Severe anemia (hemoglobin 7.0-8.9 g/dL or from baseline 4.5 g/dL)

1 (3) 1 (5)

Erythropoietin stimulating agent 3 (8) 1 (5)

Blood transfusions 4 (11) 1 (5)

Discontinuation due to AE 3 (8) 0 (0)

• No HIV breakthrough • CD4 counts declined in TVR/PegIFN/RBV and PegIFN/RBV groups • CD4% unchanged


TVR concentrations similar among patients with and without antiretroviral therapy



Efavirenz and atazanavir concentrations similar with and without telaprevir




Conclusions • Higher SVR24 rates were observed in chronic genotype 1

HCV/HIV co-infected patients treated with TVR combination therapy

– TVR/PegIFN/RBV: 74%

– PegIFN/RBV: 45%

• Drug interactions with TVR and select ART were clinically meaningful

– Increased dose of TVR with efavirenz compensated for CYP3A induction

– Telaprevir did not substantiallly modify ART exposure

– No HIV breakthroughs in patients on ART

• Overall safety and tolerability profile of TVR/PegIFN/RBV was comparable to that previously observed in HCV mono-infected patients

Timing and Magnitude of Ribavirin Dose Reduction (RBV DR) Do

Not Impact Sustained Virologic Response (SVR) Rates with

Boceprevir (BOC) + Peginterferon alfa-2b / Ribavirin (P/RBV) in the

Anemia Management Study in Chronic HCV Genotype 1 Patients

Poordad F, Lawitz E, Reddy KR, Afdhal N, Hezode C, Zeuzem S, Lee SS,

Calleja JL, Brown RS, Craxi A, Wedemeyer H, Bacon BR, Flamm SL, Deng W,

Koury KJ, Pedicone L, Dutko F, Burroughs M, Alves K, Wahl J, Brass C,

Albrecht JK, Sulkowski MS




RBV Dose Reduction for Anemia Management and

Impact on SVR Rates with Boceprevir/PegIFN/RBV

Therapy in HCV Genotype 1 HCV Patients

Objective

• To assess the impact of timing and magnitude of

ribavirin dose reduction (RBV DR) on SVR rates

in chronic HCV genotype 1 patients treated with

Boceprevir/PegIFN/RBV who develop on-

therapy anemia

Poordad F et al. Hepatology 2012; 56(Suppl S1):269A-270A.




After 4-week lead-in

with P/RBV, all

patients initiated

boceprevir.

Hb at wk 0, 2, 4, 6,

8, 10, 12, 24,

28, 34, 40, 48.

Randomized if

Hb ~10 g/dl

EPO

(n=251)

RBV DR

(n=249)

If Hb≤8.5 g/dL,

secondary

intervention

(RBV DR arm

could use EPO;

EPO arm could

use RBV DR)

If Hb>10 g/dL, patients

treated but not randomized

(n=187)

Study Design






Initial dosing

• PegIFN α-2b administered subcutaneously at 1.5 g/kg

once weekly, plus RBV using weight-based dosing of

600-1400 mg/day in a divided daily dose

Interventions for anemia

• RBV DR by increments of 200 mg at the discretion of the

investigator (first increment of 400 mg if initial dose was

1,400 mg/day)

• EPO was started at 40,000 units/wk and could be

modified at the investigator’s discretion to doses of

20,000 to 60,000 units/wk

• If Hb≤7.5 g/dL, all study drugs were discontinued




10%

71%

82%

10%

71%

82%

0

20

40

60

80

100

EOT SVR Relapse

% of Patients

RBV DR

EPO

Primary Efficacy Results

203/

249

205/

251

178/

249

178/

251 19/ 196

19/ 197





86% 86%

56% 56%

0

20

40

60

80

100

Undetectable Undetectable Detectable Detectable

RBV DR

EPO

SVRs Were Higher if Undetectable HCV RNA

at Start of Primary Anemia Management

111/

129

107/

124

67/

120 71/ 127


SVR (%)

HCV RNA at Start of Primary Anemia Management




71%

82%79%

64%70% 71%

88%

70%68%71%

0

20

40

60

80

100

>4-8 wks >8-12 wks >12-16 wks >16 wks

SVR (%)

RBV DR

EPO Use

SVR rates did not vary with the start time of anemia management

38/

54

39/

55

58/

90

60/

88


17/

24

15/

21

15/

17

18/

22

47/

67

49/

62

Timing of the start of anemia management

4 wks




83%

69%77%

64%

80%76%

67%

0

20

40

60

80

100

1 2 3 4 5 6 7

SVR (%)

SVR did not vary by number of steps* of RBV dose reduction

47/

70

44/

58

20/

25

*Step = decrease of 200 mg RBV/day for 3 days


10/

12

24/

35

23/

30

9/

14

Number of RBV DR Steps*

RBV DR arm only




33%36%

67%

77%75%70%

60%

92%

0

20

40

60

80

100

0 200 400 600 800 1000 1200 1400

SVR

(%)

SVR rates by lowest RBV dose received

for 14 days

11/

12

3/

5

28/

40


1/

3

30/

45

43/

56

58/

77

Lowest RBV dose (mg/day) for 14 days

RBV DR arm only

4/

11




92%89%

77%74%

18%

0

20

40

60

80

100

<50 50<60 60<70 70<80

SVR

(%)

SVR by Percent Total RBV Dose Received

Over the Treatment Period

10/

57

14/

19


34/

38

20/

26

Percent of total RBV dose received vs assigned RBV dose

for entire treatment period

RBV DR arm only

100/

109

80




92%89%

83%75%

67%

0

20

40

60

80

100

<50 50<60 60<70 70<80

SVR

(%)

SVR by Percent Total RBV Dose Received in Patients

Who Received ≥80% of Treatment Duration

6/

9

9/

12


34/

38

20/

24

Percent of total RBV dose received vs assigned RBV dose

for entire treatment period

RBV DR arm only

100/

109

80




Predictors of Anemia by Logistic Regression*

* Logistic Regression; Stepwise selected; All treated patients

† Normal ITPA activity = C at rs1127354 & A at rs7270101 for both haplotypes


Effect Odds Ratio 95% CI P-value

Baseline Hemoglobin

(continuous variable) 0.62 0.49 – 0.79 <0.0001

Normal ITPA Activity† 1.96 1.28 – 3.00 0.0019

Age (>40 vs ≤40) 1.98 1.19 – 3.28 0.0084

Baseline Fibrosis

(3/4 vs 0/1/2) 2.02 1.03 – 3.98 0.0421





Conclusions

• SVR rates were similar with RBV dose reduction regardless

of: 1) The timing of the first RBV reduction, 2) The number of

steps of RBV dose reductions, or, 3) The lowest RBV dose

received to manage anemia

• Similar SVRs with RBV DR or EPO if HCV RNA was

detectable at time of anemia management; similar SVRs with

RBV DR or EPO if HCV RNA was undetectable at time of

anemia management

• SVR rates were lower if <50% of the intended total RBV dose

assigned per-protocol was administered

• RBV dose reduction is the preferred first strategy for anemia

management

OPTIMIZE Trial: Non-Inferiority of Twice-Daily

Telaprevir Versus Administration Every 8 Hours in

Treatment-Naïve, Genotype 1 HCV Infected Patients

Buti M, Agarwa K, Horsmans YJ, Sievert W, Janczewska E, Zeuzem S, Nyberg L,

Brown RS, Hezode C, Rizzetto M, Paraná R, De Meyer S, Luo D, Witek J

Abstract LB8, AASLD 2012



Twice-daily Telaprevir vs. Administration Every 8 Hours

in Treatment-Naïve Genotype 1 HCV Patients

Objective

• To investigate the use of telaprevir (TVR) twice

daily (bid) vs. every 8 hours (q8h) in combination

with PegIFN/RBV in treatment-naïve patients

with chronic genotype 1 HCV infection

Buti M et al. Abstract LB-8. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012




TVR +

PegIFN +

RBV

Peg-IFN +

RBV

Peg-IFN + RBV

TVR +

PegIFN +

RBV

Peg-IFN +

RBV

Peg-IFN + RBV

T12 (750 mg q8h)/PR (N=371)

T12 (1125 mg bid)/PR (N=369)

RVR+

RVR-

RVR+

RVR-

Follow-up Follow-up

Follow-up Follow-up

Optimize Study Design

Follow-up

Follow-up

0 12 24 36 48 60 72 Time (weeks)




74%74%73%

0

20

40

60

80

100

T12(q8h)/PR T12(bid)/PR All patients

270/ 371

274/ 369

544/ 740

SVR12 (%)

Efficacy: SVR12




65%68%

87%

66%68%

92%

65%68%

90%

0

20

40

60

80

100

CC CT TT

92/ 106

141/ 208

37/ 57

SVR12 (%)

Efficacy: SVR12 by IL28B Genotype

97/ 105

189/ 211

139/ 206

280/ 414

38/ 58

75/ 115

IL28B Genotype

T12(q8h)/PR

T12(bid)/PR

All patients




59%

78%

58%

81%

59%

79%

0

20

40

60

80

100

F0-F2 F3-F4

209/ 268

61/ 103

SVR12 (%)

Efficacy: SVR12 by Liver Disease Status

213/ 264

422/ 532

61/ 105

122/ 208

Liver Disease Status

T12(q8h)/PR

T12(bid)/PR

All patients



*SSC=Special search category: Grouped AE terms representing similar medical concepts


Adverse event, n (%)

T12(q8h)/PR

(N=371)

T12(bid)/PR

(N=369)

All patients

(N=740)

Any adverse event 367 (99) 360 (98) 727 (98)

Serious adverse event

Death

35 (9)

1 (<1%)

28 (8)

0

63 (9)

1 (<1%)

Any Grade 3 adverse event

Grade 3 anemia SSC*

Grade 3 rash SSC*

139 (38)

70 (19)

22 (6)

156 (42)

95 (26)

18 (5)

295 (40)

165 (22)

40 (5)

Any Grade 4 adverse event 24 (7) 23 (6) 47 (6)

Any adverse event leading to

permanent discontinuation of TVR

69 (19) 57 (15) 126 (17)

Any treatment-related adverse event

considered possibly related to TVR

335 (90) 344 (93) 679 (92)

Adverse events during the TVR treatment phase



*Adverse events occurring in >25% in all patients in any group SSC=Special search category: Grouped AE terms representing similar medical concepts


Most frequent AEs, n (%)*

T12(q8h)/PR

(N=371)

T12(bid)/PR

(N=369)

All patients

(N=740)

Fatigue 177 (48) 173 (47) 350 (47)

Pruritus SSC 171 (46) 170 (46) 341 (46)

Anemia SSC 162 (44) 167 (45) 329 (45)

Nausea 142 (38) 128 (35) 270 (37)

Rash SSC 199 (54) 189 (51) 388 (52)

Headache 107 (29) 87 (24) 194 (26)

Adverse events during the TVR treatment phase




Conclusions

• SVR12 rates for TVR 1125 mg bid were noninferior to

TVR 750 mg q8h (74% vs. 73%, respectively)

• SVR 12 outcomes for T12(bid)/PR and T12(q8h)/PR

were similar regardless of liver fibrosis status and IL28B

genotype

• The safety and tolerability profile of T12(bid)/PR and

T12(q8h)/PR was similar between treatment groups

• Similar SVR and AE rates achieved with 1125 mg bid

TVR and 750 mg q8h TVR offers the potential of a

simplified dosing regimen for genotype 1 HCV patients

Treatment of Hepatitis C Genotype 1 Patients with

Severe Fibrosis or Compensated Cirrhosis: The

International Telaprevir Early Access Program

Colombo M, Fernández I, Abdurakhmanov D, Abrão Ferreira PR, Strasser SI,

Urbanek P, Moreno C, Streinu-Cercel A, Verheyen A, Iraqi W, DeMasi R, Hill A,

Läuffer JM, Lonjon-Domanec I, Wedemeyer H

Abstract LB-15, AASLD 2012




Severe Fibrosis or Compensated Cirrhosis With

Telaprevir/PegIFN/RBV: Interim Analysis

Objective

• To assess efficacy and safety of telaprevir (TVR)

in combination with PegIFN/RBV in treatment

naïve and treatment experienced patients with

genotype 1 hepatitis C with severe fibrosis or

compensated cirrhosis

Colombo M et al. Abstract LB-15. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012




Methods

• Required at entry: Liver biopsy or noninvasive tests

showing severe fibrosis (Metavir F3 or Ishak 3-4) or

cirrhosis (Metavir F4 of Ishak 5-6) and platelet count

>90,000/mm3

• Inclusion criteria: Genotype 1, severe fibrosis (F3) or

compensated cirrhosis (F4)

• 1,900 patients recruited to date; first 609 patients with

data to week 16 included in interim analysis





Methods (cont)

• Patients were treated with telaprevir 750 mg every 8

hours (q8h) and PegIFN/RBV (dosed according to label)

for 12 weeks

– Treatment-naïve or prior treatment relapsers: After week 12,

PegIFN/RBV was given for an additional 12-36 weeks,

depending on the initial virological response observed

– Previously treated patients with prior partial or prior null

response: After week 12, PegIFN/RBV was given for an

additional 36 weeks






Treatment-naïve or prior treatment relapsers

Telaprevir 750

mg q8h +

PegIFN/RBV

PegIFN/RBV Follow-up

PegIFN/RBV Follow-up

Previously treated with prior partial or prior null response

Telaprevir 750

mg q8h +

PegIFN/RBV

PegIFN/RBV

Follow-up

Study Design

0 12 24 48 72

Time (weeks)




Baseline characteristics

• Treatment-naïve: 20%

• Prior relapsers: 28%

• Prior partial responders: 15%

• Prior null responders: 29%

• Non-responders (unspecified): 3%

• Prior viral breakthrough: 5%

• HCV RNA levels 800,000 IU/mL: 66%

• Severe fibrosis: 45%

• Cirrhosis: 55%

• HCV genotype 1a: 28%






77%82%

68%

80%80%86%

54%

68%

41%

52%

63% 59%

0

20

40

60

80

100

Naive Relapser Partial

Responder

Null

Responder

Viral

Breakthrough

Overall

Week 4 Viral Response

Patients (%)

HCV RNA <25 IU/mL

HCV RNA not detected

(n=124) (n=171) (n=94) (n=176) (n=28) (n=609)





83%89%

76%

85%87%88%

79%

86%

68%

77%

85% 85%

0

20

40

60

80

100

Naive Relapser Partial

Responder

Null

Responder

Viral

Breakthrough

Overall

Week 12 Viral Response

Patients (%)

HCV RNA <25 IU/mL

HCV RNA not detected

(n=124) (n=171) (n=94) (n=176) (n=28) (n=609)




Anemia • Patients developing anemia up to week 16

– Grade 1-4 anemia (Hb <11 g/dL or >2.5 g/dL ): 359/609 (59%)

– Grad 3 or Grade 4 anemia (Hb <9 g/dL or >4.5 g/dL ): 189/609

(31%)

• Management of anemia

– Reduced RBV dose: 171/609 (28%)

– Received erythropoietin: 148/609 (24%)

– Received transfusions: 70/609 (11.5%)

– Discontinued TVR treatment due to anemia: 19/609 (3%)








F3

(n=273)

F4

(n=335)

All

(n=609)

Subjects with one or more Grade

2 or higher treatment related AEs

171 (62.6) 247 (73.7) 418 (68.6)

Anemia SSC 101 (37.0) 172 (51.3) 273 (44.8)

Rash SSC 42 (15.4) 52 (15.5) 94 (15.4)

Thrombocytopenia 15 (5.5) 45 (13.4) 60 (9.9)

Pruritus SSC 19 (7.0) 32 (9.6) 51 (8.4)

Asthenia 23 (8.4) 27 (8.1) 50 (8.2)

Nausea 12 (4.4) 24 (7.2) 36 (5.9)

Anorectal SSC 14 (5.1) 21 (6.3) 35 (5.7)

Grade 2-4 drug-related AEs ( 5%) by fibrosis stage--until week 16







F3

(n=273)

F4

(n=335)

All

(n=609)

Subjects with one or more AEs

leading to discontinuation

32 (11.7) 53 (15.8) 85 (14.0)

Rash SSC 15 (5.5) 15 (4.5) 30 (4.9)

Anemia SSC 3 (1.1) 16 (4.8) 19 (3.1)

Asthenia 3 (1.1) 4 (1.2) 7 (1.1)

Abdominal pain 1 (0.4) 5 (1.5) 6 (1.0)

Nausea 3 (1.1) 3 (0.9) 6 (1.0)

Pruritus SSC 1 (0.4) 5 (1.5) 6 (1.0)

Vomiting 4 (1.5) 2 (0.6) 6 (1.0)

Discontinuation of TVR due to AEs: Reported by 1% of patients-- until week 16





Conclusions

• A treatment week 16 interim analysis of 609

patients with severe fibrosis or compensated

cirrhosis treated with TVR/PegIFN/RBV found:

– 79% had undetectable HCV RNA by week 12

– HCV RNA responses at week 12 were lower for prior

null responders compared with treatment-naïve

patients, prior relapsers or prior partial responders

– Serious AEs occurred in 14% of patients and

discontinuation due to anemia or rash was similar to

Phase III registration trials

hcv highlights from aasld 2012 - chronic liver disease foundation

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