Boceprevir-based therapy adverse events :

Case studies

Marc Bourliere , MD International symposium

Hôpital Saint Joseph 5-7 June 2014

Marseille, France St Petersburg

Disclosures

– Board member for : Schering-Plough, Merck, Janssen, Gilead, Boehringer Ingelheim, BMS, Novartis, Roche, Abbott, GSK, Vertex, Idenix

– Speaker for : Roche, Schering-Plough, Merck, Janssen, Gilead, BMS, Abbvie

Clinical Case

• Mr W 66 yo male, HCV cirrhosis genotype 1a, treatment failure in 2003, weight 85kg, BMI 29, type 2 diabetes

• Concomitant medication : Atorvastatin , metformin

• Prior treatment response : 2003 – Pegasys 180 µg / w + 1200mg/d Ribavirin

– W-4 : HCV RNA : 7,2 Log UI/ml

– W12 : HCV RNA positive (Cobas amplicor®)

– W24 : HCV RNA Positive : treatment was discontinued

Clinical Case

• No prior history of liver decompensation , no oesophageal varices

• Laboratory values : – AST : 90 IU/ml, ALT : 80 IU/ml, GGT: 75 IU/ml, AP: 60 IU/ml, Total

Bilirubin: 30 µmol/l , Albumin : 35g/l, PT: 85%, AFP : 50 ng/ml

– Platelets : 100,000, Hb : 11 g/dl WBC : 6000

– HCV RNA : 6.1 log10 IU/ml (MELD 9)

• FibroTest : A2F4, Fibroscan : 19 KpA IQR: 2 SR 85%

• Ultrasound : enlarge fatty liver , normal PV blood flow , splenomegaly, no ascites, no HCC

Do we need to treat this patients ?

Survival Outcomes in Patients With CHC and Advanced Hepatic Fibrosis With and Without SVR

Van der Meer AJ, et al. JAMA 2012

60

Cumulative development rate of HCC in HCV-infected patients treated with IFN

Retrospective cohort of 4302 Japanese patients treated with IFN-a followed for average 8.1 years

Cumulative incidence of HCC: 4.3% at 5 years, 10.5% at 10 years, 19.7% at 15 years

T2DM caused 1.73-fold increase in HCC

Arase Y et al, Hepatology 2013;57:964−973

0

10

20

30

40

50

0 10 20 30

Diabetes

Non-diabetes 24.5%

9.3%

HbA1c ≥7.0

HbA1c <7.0

27.9%

21%

60

0

10

20

30

40

50

0 10 20 30

p<0.001 p=0.015

Year of follow up Year of follow up

Cu

mu

lati

ve d

ev

elo

pm

en

t ra

te o

f H

CC

(%

)

Cu

mu

lati

ve d

ev

elo

pm

en

t ra

te o

f H

CC

(%

)

HCC, hepatocellular carcinoma; IFN, interferon;

SVR, sustained virological response; T2DM, type 2 diabetes

Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCV-induced (stage 1) cirrhosis according to response to therapy

Bruno S, et al. Hepatology 2010

The Impact of SVR on the “de novo” Development of Esophageal Varices: Pre-primary Profilaxis

100

60

40

80

0 PRE-TREATMENT POST-TREATMENT

NU

MB

ER O

F PA

TIEN

TS (

%)

38 2 7

15

14 20

Cirrhosis Regression in 23 (61%) Patients

F4

F3

F2

F1

F0

D’Ambrosio R, et al. Hepatology 2012

Metavir

Rates of Cirrhosis Regression According to the METAVIR Scoring System

Post hoc analysis of the MIST study

Efficacy of triple therapy in treatment-experienced patients: clinical trials versus real life

Poordad F, et al. N Engl J Med 2011;364:1195–206 Calleja JL, et al. AASLD 2013. Abstract 1885

Fontaine H, et al. AFEF 2013

F0–4 F4 F0–4 F4 F0–4 F4

Clinical

EAP/cohort

RESPOND-2 CUPIC RESPOND-2 CUPIC PROVIDE CUPIC

BOC

F3/F4 F3/F4 F3/F4

Spanish

EAP

Spanish

EAP

Spanish

EAP

0

20

60

100

40

80

SV

R (

%)

Relapsers Partial responders Null responders

105 57 50 42 54 102 94 52 N=

Serious adverse events during triple therapy – clinical trials versus real life*

*Cross-comparison of studies cannot be carried out Proportion of cirrhotic patients in TARGET: TVR: 45%; BOC: 30% APRI: AST to platelet ratio index

1. Jacobson I, et al. N Engl J Med 2011;364:2405–16; 2. Poordad F, et al. N Engl J Med 2011;364:1195–206 3. Zeuzem S, et al. N Engl J Med 2011;364:417–28; 4. Bacon BR, et al. N Engl J Med 2011;364:1207–17

5. Fontaine H, et al. AFEF 2013; 6. Colombo M, et al. AASLD 2012. Abstract LB-15 7. Calleja JL, et al. AASLD 2013. Abstract 1885; 8. Di Bisceglie AM, et al. AASLD 2013. Abstract 41

9. Mauss S, et al. AASLD 2013. Abstract 1856; 10. Berg, et al. AASLD 2013. Abstract 1900

ADVANCE1 SPRINT-22 REALIZE3

Registration trials

RESPOND-24

Oc

cu

rre

nc

e o

f S

AE

s (

%)

CUPIC5

F0–4 F4 F3/F4 F0–F4 APRI >1.5

EAP and post-marketing cohorts

F0–4

TVR-EAP6 TARGET8 PAN9 TEPS10

Telaprevir

Boceprevir

Combined

0

20

40

60

9 12

54

12 12 14

12

16 18

44

F3/F4

35

BOC-EAP

(Spanish

patients)7

Adverse events with Boceprevir in phase II / III studies

Manns M et al. Liver Int 2014; 34: 707-719

PR BOC/PR

Patients, n

(% patients with at least one event)

Telaprevir n = 299 Boceprevir n=212

Serious adverse events (SAEs)* 161 patients

(53.8%)

94 patients

(44.3%)

Premature discontinuation /

due to SAEs

134 (44.8%) /

71 (23.8%)

95 (44.8%)/

37 (17.5%)

Death 8 (2.7 %) 3 (1.4%)

Infection (Grade 3/4) 29 (9.7 %) 8 (3.8%)

Hepatic decompensation

(Grade 3/4)

14 (4.7 %) 9 (4.2%)

Anemia (Grade ¾ : Hb < 8 g/dL) 38 (12.7 %) 19 (9%)

Rash (grade 3/SCAR) 16 (5.3 %)/ 0 (0 %) 2 (0.9%)/0

EPO use /

blood transfusion / RBV red or

disc

169 (57 %) /

53 (18 %) / 83 (28%)

119 (56.1%) /

25 (11.8%)/ 50(24%)

GCSF use 2 (0.7 %) 6 (2.8%)

* SAEs in patients; SCAR: severe cutaneous adverse reaction

SVR12 safety findings

Fontaine H , France, AFEF 2013,

SAE according to age

Hézode C, et al. AASLD 2013

Liver

Décompen

%

pati

en

ts

Grade 3/4

infection

0

5

10

15

20

2

4

9

12

4

6

<65 years

≥65 years

5/221 3/78 20/221 9/78 9/221 5/78

p=NS p=NS p=NS

Death

TELAPREVIR

Liver

Décompen

%

pati

en

ts

Grade 3/4

infection

0

5

10

15

20

2

0 3

7

2

14

<65 years

≥65 years

3/168 0/44 5/168 3/44 3/168 6/44

p=NS p=NS P=0.003

Death

BOCEPREVIR

Question 1 ?

• Which baseline criteria do you take into account to decide treatment in this cirrhotic patient ?

– Platelets

– Prothrombin time ratio, INR

– Bilirubin

– Albumin

– AST/ALT ratio

– Creatinin

– MELD score

– Past history of hepatic decompensation

Multivariate analysis: baseline

predictors of sustained virological

response

Predictors

OR 95%CI p-value

Relapse vs

Partial response

2.96

1.97-4.44

<0.0001

Null response vs

Partial response

0.28 0.11-0.73 0.0086

Genotype 1b vs 1a 2.50 1.62-3.85 <0.0001

Platelets > 100,000/mm3 2.15 1.34-3.45 0.0015

No lead-in phase 1.78 1.20-2.66 0.0044

Albumin ≥ 35g/L 1.86 0.97-3.56 0.06

Fontaine H .al. AFEF 2013,

Sultanik P et al. EASL 2013

Baseline ApolipoproteinH (ApoH) is a predictor of early virologic response to triple therapy (ANRS-CO20-CUPIC)

Biomarkers in Hepatitis C – DAA1

CUPIC – ANRS CO20 plasma biomarkers

0

2

4

6

8

10

- Log

10 (

p)

AFP

TTR

apoH

apoCIMCSF

IL6rb

EVR

SVR

Cyt

okines

Chem

okines

Gro

wth

fact

ors

Tissu

e re

model

ing p

rote

ins

Apolip

oprote

ins

Met

abolic p

rote

ins

Horm

ones

Can

cer m

arke

rs

Oth

er p

lasm

a pro

tein

s

0.0 0.2 0.4 0.6 0.8 1.0 0.0

0.2

0.4

0.6

0.8

1.0

AUC = 0.77

Se = 66%, Sp = 72%

PPV = 68%, NPV =70%

ROC curve of apoH-based model for SVR

High basal Apolipoprotein H is associated with SVR

Sultanik & al., submitted

CUPIC: identifying high-risk patients

• CUPIC enrolled treatment-experienced patients with compensated cirrhosis and notable risk factors

– Patients achieved high rates of SVR with TVR or BOC in combination with PR

• Patients with cirrhosis who present with significant risk factors require careful monitoring when being treated with PR

Fontaine H, et al. AFEF 2013

Platelets count

≤100,000/mm3

Platelets count

>100,000/mm3

Albumin

<35 g/L

N

Complications, n (%)

SVR12, n (%)

37

19 (51.4%)

10 (27.0%)

31

5 (16.1%)

8 (29.0%)

Albumin

≥35 g/L

N

Complications, n (%)

SVR12, n (%)

74

9 (12.2%)

27 (36.5%)

306

19 (6.2%)

168 (54.9%)

CUPIC data confirmed in ongoing studies

Mauss S, et al. AASLD 2013. Abstract 1856

The risk of SAEs was 28.6% in patients with platelet count <100 x109/L and serum albumin <35 g/L, thus

confirming the findings from the CUPIC study

SAEs by platelets and albumin at baseline

This evaluation is part of a large,

ongoing German multi-centre

observational study including adults

with detectable HCV RNA

<100

<35

<100

≥35

≥100

≥35

≥100

<35

X109/L

g/L

Platelets:

Albumin:

SA

Es (

%)

4.8%

(n=1/21)

0%

(n=0/7)

8.5%

(n=4/47)

28.6%

(n=2/7)

HCV-TARGET: Risk Factors for Poor

Outcomes in PI-Treated Pts

• Risk factors for decompensation

among cirrhotic patients during

PI therapy identified[1]

• Pts with history of

decompensation at highest risk

for SAEs with PIs[2]

1. Afdhal N, et al. AASLD 2013. Abstract 1865. 2. Gordon S, et al. AASLD 2013. Abstract 1866.

Pa

tie

nts

(%

)

Baseline Characteristic

Odds Ratio Minimally Adjusted Estimates

P Value

CrCl (mL/min) 0.99 .03

Albumin (g/dL) 0.30 < .01

HCV RNA (log IU/mL)

0.76 < .01

Bilirubin (log mg/dL)

2.93 .02

100

80

60

40

20

0 SAE Decomp

AE Decomp

SAE Completed Treatment

Noncirrhotics (n = 639) Cirrhotics w/prior decomp’n (n = 49) Cirrhotics w/o prior decomp’n (n = 412)

10

33

12

1

24

7 0

10 1

71

43

55

Clinical Case

● June 2012: pegIFN /RBV 1200 mg/d was initiated ● HCV RNA : 1.5 106 IU/ml Hb: 12g/dl

● W2 : Hb : 11g/dl

● W4 : Hb : 10.1 g/dl, Albumin : 35 g/l, Bilirubin : 35 μmol/l , HCV RNA : 5 104 IU/ml

0

10

20

30

40

50

60

70

80

90

100

125/198 30/101

RVR

NO

RVR

63%

40%

P < 0.001

TELAPREVIR

0

10

20

30

40

50

60

70

80

90

100

62/99 29/113

HCV RNA

Decline

≥ 1log

W4

RVR

W8

63%

26%

BOCEPREVIR

Fontaine H , France, AFEF 2013,

SVR12 according to on-treatment response

HCV RNA

Decline

< 1log

W4

NO

RVR

W8

HCV RNA

Decline

< 3log

W8

58/81 33/131

72%

25%

4/63

6%

P < 0.001 P < 0.001

Question 2 ?

• How do you manage anemia at this stage ?

– EPO use

– Ribavirin dose reduction

– Both EPO and RBV dose reduction

– Peg-IFN dose reduction

– Nothing

Anemia management according to age

Hézode C, et al. AASLD 2013

BOCEPREVIR

0

10

20

30

40

50

60

<65 years

≥65 years

7

18

10

20

53

68

p=0.032 p<=0.063

p=0.088

Grade 3/4 Transfusions EPO

Anemia

70

80

11/168 8/44 16/168 9/44 89/168 30/44

SVR according to time of first RBV dose reduction during first 4 weeks of treatment and HCV RNA status

Treatment-naïve patients in ADVANCE/ILLUMINATE (N=885) Sulkowski MS, et al. J Hepatol 2012;56(Suppl. 2):S459–60

Pati

en

ts w

ith

SV

R (

%)

Undetectable HCV RNA Detectable HCV RNA

40

45

347

405

120

176

168

259

Small sample sizes among previously treated patients limit interpretation of data in REALIZE,

however similar trends were observed

Boceprevir: similar SVR when RBV dose modification and EPO are used to manage anemia

178

249

178

251

Treatment-naïve G1 patients (n=687) received BOC-based therapy. Overall, 500

patients developed anemia (Hb ≤10 g/dL or were expected to reach that nadir

before next visit) and were randomized to have anemia managed with either

EPO (40 000 units/week SC), or RBV dose reduction (by 200–400 mg/day).

Transfusion in patients with Hb ≤8.5 g/dL was allowed to prevent study

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

Genotype 1 cirrhosis and boceprevir : RBV dose reduction or EPO use ?

SVR according to

RBV DR or EPO use

RBV DR : RBV dose reduction

SV

R (

%)

SVR according to the need

of single or double strategy

57 64

RBV

DR

13/23

EPO

16/25 S

VR

(%

)

52

71

14/27

Do

ub

le

str

ate

gy

15/21

Sin

gle

str

ate

gy

Lawitz E, Etats-Unis, AASLD 2012, Abs. 50 actualisé

Predictors of severe anaemia < 8 g/dl or BT

Multivariate analysis: baseline factors related to anaemia<8g/dl or blood transfusion

Hezode et al AASLD 2012 Abs 51

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

Clinical Case

● We reduced RBV dose down to 1000 mg/d add EPO W6: Hb : 10.5 g/dl , HCV RNA : 500 IU/mL

● W8: Hb : 9.5 g/dl, HCV RNA <12 IU/mL, albumin : 34 g/l , bilirubin: 35 μmol/l. Asthenia and anaemia were managed by EPO ( neorecormon 30.000 UI/w) and RBV dose reduction down to 800 mg/d

0

10

20

30

40

50

60

70

80

90

100

125/198 30/101

RVR

NO

RVR

63%

40%

P < 0.001

TELAPREVIR

0

10

20

30

40

50

60

70

80

90

100

62/99 29/113

HCV RNA

Decline

≥ 1log

W4

RVR

W8

63%

26%

BOCEPREVIR

Fontaine H , France, AFEF 2013,

SVR12 according to on-treatment response

HCV RNA

Decline

< 1log

W4

NO

RVR

W8

HCV RNA

Decline

< 3log

W8

58/81 33/131

72%

25%

4/63

6%

P < 0.001 P < 0.001

• Guidelines recommend BOC-based triple therapy

EASL guidelines: BOC treatment algorithm

*In the BOC SmPC label there is no response-guided therapy for treatment-experienced patients and patients with cirrhosis ER: early response; LR: late response EASL Clinical Practice Guidelines. J Hepatol 2014;60:392420

Detected LR

Undetected

Detected

<100 IU/mL

Detected

>100 IU/mL

Undetected

Undetected

Undetected

Detected

28 weeks of

therapy*

0 4 8 12 24 28

48 weeks of

therapy

Undetected

ER

PR PR + BOC

Week

HCV

RNA

Stop Stop

Interest of RGT for reducing adverse events

Manns M et al. Liver Int 2014; 34: 707-719

Clinical Case

● W12: Hb : 10.7g/dl , HCV RNA undetectable , albumin : 32 g/l , bilirubin: 37 μmol/l.

● W24 : Hb : 11g/dl, platelet count 60,000/μl, HCV RNA undetectable , albumin : 31 g/l, bilirubin 39 μmol/l.

● W36 : Hb : 10,7g/dl, platelet count 55,000/μl, HCV RNA undetectable , albumin : 30 g/l, bilirubin 39 μmol/l.

● W40 : Ascites, spontaneous bacterial peritonitis (caused by E. coli) and deep asthenia resulted in cessation of treatment

Clinical case

• SBP was cured by cefotaxim

• Ascites resolved with albumin and diuretic

• Patient did not relapsed

• MELD increase to 12

• Liver transplant assessment was done

Should we use prophylactic antibiotic in this setting ?

HCV decompensated cirrhosis treatment with PEG-

IFN / RBV : Usefulness of norfloxacin prophylaxis

Carrion JA et al. J Hepatol 2009; 50: 719-728.

Laboratory abnormalities in pooled data from the placebo-controlled Phase II and Phase III studies

• With TVR treatment, most laboratory values return to levels observed with Peg-IFN/RBV by Week 24

– The exception was platelet count, which remained at levels lower than observed with Peg-IFN/RBV until Week 48

• The addition of BOC to Peg-IFN/RBV was associated with higher incidences of increased uric acid, triglycerides and total cholesterol compared with Peg-IFN/RBV only

Telaprevir EU SmPC; Boceprevir EU SmPC

TVR/PR BOC/PR

Uric acid Increase Increase

Bilirubin Increase

Total cholesterol Increase Increase

Triglycerides Increase

Creatinine Increase

Hemoglobin Decrease Decrease

Platelet count Decrease Decrease

Absolute lymphocyte count Decrease Decrease

Potassium Decrease Decrease

PAN cohort: decrease of eGFR in patients with >60 mL/min at baseline to ≤60 mL/min after 12 weeks

• Increased serum creatinine levels were observed in registration trials

eGFR: estimated glomerular filtration rate Telaprevir SmPC

Mauss S, et al. Hepatology 2014;59:46–8

Risk factors: age, arterial hypertension, diabetes mellitus, higher serum creatinine at baseline and triple therapy

TVR/PR BOC/PR PR

38/575 10/211 1/109

Pa

tie

nts

(%

)

Key learnings: a summary

• Anemia was commonly seen in real-life cohorts and should be managed early

with RBV dose reduction

– Does not impact SVR with TVR or BOC

– During TVR dosing, the timing of RBV dose reduction does not appear to impact SVR1

Older patients can still be effectively treated with TVR and BOC but are at greater

risk of anemia, rash and SAEs2,3

• Patients with risk factors for renal impairment receiving triple therapy are at greater risk of impaired renal function than patients receiving PR. Changes to renal function are typically temporary4

1. Bourliere M, et al. AASLD 2013. Abstract 1895; 2. Moreno C, et al. AASLD 1911 3. Hezode C, et al. AASLD 2013. Abstract 1845; 4. Mauss S, Hepatology 2014;59:46–8

Predictors of anemia and anemia management

Outcomes and management in elderly patients

Creatinine fluctuations on triple therapy

Telaprevir:1 Boceprevir:2

Counselling should be provided on potential adverse events that may occur

1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC

Telaprevir:1 Boceprevir:2

Anemia

Nausea

Rash, pruritus

Anorectal signs/symptoms

Diarrhea

Anemia

Nausea

Dysgeusia

Neutropenia

Headache

Ribavirin doses should be reduced early to minimise the impact of anemia

Child-Pugh: A B C

Number of patients

Efficacy of treatment

Prevalence and severity of side effects

Efficacy of antiviral therapy and side effects in relation to severity of disease

Use of PEG/RBV for pre transplant treatment to prevent post transplant recurrence

Authors Patients, N HCV RNA negative Day of LTX

pTVR

Carrion 51 29% 20%

Everson 47 32% 26%

Forns 30 30% 20%

Thomas 20 60% 20%

Everson (LADR-A2ALL) 44 59% 25%

GT 1/4/6 23 52% 22%

GT 2/3 21 67% 29%

Totals 192 40% 24%

Burton JR , Everson GT Clin Liv Dis 2013; 17: 73-91

Side effects were common and serious

even life-threatening complications occured

Likelihood of achieving pTVR is related to treatment duration

Everson GT, et al. Hepatology 2012

Protease-Inhibitor (PI) Triple Therapy (TT) in Cirrhotics with Compensated and Mildly Decompensated Disease:

Implications for Wait-Listed Patients

45 G1 HCV Cirrhotics

(7 wait-listed for OLT)

PR + BOC (24%)

PR + TPV (76%)

On-treatment VR:

≈40%

RVR associated with:

•Prev. Naive

•Prev. Relapser

•LVL

PI type: no prediction of

VR

Saxena V, et al. AASLD 2012

Summary and conclusions • DAAs have been shown to significantly improve SVR rates,

however there are patient management considerations

– AEs such as anemia and rash are common with triple therapy

– Effective management of these events is key to treatment success

• Early recognition of AEs through clinical monitoring is an important component of patient management

• The main components for these achievements are

– Doctor’s skill deriving from training and practice

– Patient’s awareness from practical guidance and counselling

Conclusion

• Cirrhotic patients are the most in needed for HCV treatment.

• Child Pugh A patients should be treated

• More advance cirrhosis should be treated with caution on a case by case basis

• Patients with platelets < 100,000 and albumin< 35g/l should not be treated