professor graham foster · 12/12/2014 1 in partnership with queen mary, university of london, uk...

12/12/2014

1

in partnership

with

Queen Mary, University of London, UK

Professor Graham Foster

Pre-conference Clinical Course

in partnership

with

COMPETING INTEREST OF FINANCIAL VALUE > £1,000

Statement

Professor Graham Foster has received consultancy and speaker fees

from BI, BMS, AbbVie, Janssen, GSK, Gilead, Merck, Roche, Springbank,

Achillion and Novartis.

Date: December 2015

Queen Mary, University of London, UK

Professor Graham Foster

Pre-conference Clinical Course

12/12/2014

2

End Stage Liver Disease

Graham R Foster

Professor of Hepatology

Queen Marys University of London

Disclaimer

• I have received fees from BI, BMS, Gilead,

Merck, Janssen, Novartis, Roche, Springbank,

Idenix

• The views expressed are my own

12/12/2014

3


• Numbers

• Decompensation

• Cancer

• Therapeutic options


• Numbers

• Decompensation

• Cancer


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• PHE estimate that around 10,000 patients

with HCV have cirrhosis

• A proportion per year will develop HCC and/or

decompensate

Systematic review: outcome of compensated

cirrhosis due to chronic hepatitis C infection

Alazawi et al Alimentary Pharmacology & Therapeutics

Volume 32, Issue 3, pages 344-355, 22 MAY 2010 DOI: 10.1111/j.1365-2036.2010.04370.x

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04370.x/full#f1

No therapy Therapy

Death/OLT per year 4.62% 3.79%

HCC per year 4.79% 2.52%

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Copyright © 2014 American Medical Association. All rights reserved.

From: The Risk of Long-term Morbidity and Mortality in Patients With Chronic Hepatitis C: Results From an

Analysis of Data From a Department of Veterans Affairs Clinical Registry

JAMA Intern Med. 2014;174(2):204-212. doi:10.1001/jamainternmed.2013.12505


A growing problem

• Hospital admissions and deaths related to

HCV: England.1

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Worse before it gets better


• Numbers

• Decompensation

• Cancer


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• Decompensation:-

ascites/encephalopathy/bleed

• Unpredictable

• Often sepsis associated

• Need hepatological input

Decompensation - Prevention

• Avoid futile drugs (benzos, PPIs, NSAIDS)

• Warn patients of risks

• Regular endoscopies

• ?? Anti-coagulation

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• Numbers

• Decompensation

• Cancer


End Stage Liver Disease - HCC

• Most feared complication

• Increasing treatment options for early

malignancy

• Catch it early – scan every 6 months

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• Numbers

• Decompensation

• Cancer


Telaprevir SVR rates by fibrosis stage in

treatment-naïve patients

SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after last planned dose Marcellin P, et al. J Hepatol 2011;54(Suppl 1):S183

SV

R (

%)

PR48

67/147n/N=

T12PR

109/134

PR48

67/141

T12PR

117/156

F0–F1 F3

PR48

17/52

T12PR

32/52

F4

T12PR

13/21

PR48

7/21

F2

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Barts & London Experience

• Early audit of Protease Inhibitors

• 29 Genotype 1 patients treated with triple

therapy

29 pts TVR (24 pts ) BOC ( 6 pts)

Gender % male 79%

Mean age 53.8 yrs

Treatment exp 15 relapse (51%)

7 non-responders( 24 % )

7 naiive ( 24 % )

Varices 10 (34%)

7 (24 %) not known

Haemoglobin 14.25 (17.2-12.5)

Platelets 137 (210 – 43)

Albumin 43 (50 - 34)

Creatinine 74

Baseline Characteristics

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48% premature discontinuation

Outcomes


3/29 (10 %) futility rules

2/29 (6.8 %) viral break through

9/29 (31%) stopped due to side effects

Outcomes

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3/29 (10 %) futility rules

2/29 (6.8 %) viral break through

9/29 (31%) stopped due to side effects

3 decompensated

3 rash

1 DDI

2 sepsis ( 1 death )

Outcomes

7/29 ( 24 % ) have achieved SVR

1/29 (3.4 %) relapsed post treatment

7/29 (24 %) - treatment is ongoing

- all currently viral negative

Virology

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7/29 ( 24 % ) have achieved SVR

1/29 (3.4 %) relapsed post treatment

7/29 (24 %) - treatment is ongoing

- all currently viral negative

We killed 1, we cured 7

This is NOT a good average

Virology

Adverse Events with 12 weeks Peg/Riba

G3 cirrhosis study with Peg/Riba

Time to withdrawal –

Patients randomised to 24

weeks

Time to withdrawal –

Patients randomised to 48 weeks

First 12

weeks

Weeks

13- 24

During

follow

up

First 12

weeks

Weeks

13-24

Weeks

25 - 48

During

follow

up

Withdrawn for AE2 2 0 3 4 4 1

(Died)

Withdrawn patient

request/lost to

follow up

0 0 1 2 2 3 4

Withdrawn for lack

of efficacy (viral

load increase >1 log

on therapy)

0 2 0 0 0 1 0

Total withdrawals2 4 1 5 6 8 5

1 death, 4 SAEs in first 12 weeks (4% SAE)

Shoeb et al STEPS Study J Hep 2014

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The ‘Old Drugs’

• Very hard to use in patients with cirrhosis

• High failure rate

• High serious adverse event rates

The New Drugs

• How do they behave in cirrhosis?

• The pivotal clinical trials had relatively few

patients with cirrhosis

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An Integrated Safety and Efficacy Analysis of >500 Patients

with Compensated Cirrhosis Treated with LDV/SOF±RBV

• 513 patients with HCV GT 1, compensated cirrhosis

• Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies

– LONESTAR, ELECTRON, ELECTRON-2, Japan phase 3 study, ION-1, ION-2, SIRIUS

• Primary efficacy endpoint: SVR12

Wk 0 Wk 12 Wk 36Wk 24

SVR12LDV/SOF

SVR12LDV/SOF + RBV

SVR12LDV/SOF + RBV

SVR12LDV/SOF

n=118

n=204

n=133

n=58

Bourliere, AASLD, 2014, Oral #82

SV

R1

2 (

%)

305/322 188/191

12 Weeks 24 Weeks

LDV/SOF ± RBV, N=513

Results: SVR12 by Treatment Duration

SVR rates were similar with 12 or 24 weeks of LDV/SOF ± RBV


Error bars represent 95% confidence intervals.

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Overall SVR12

Duration12 wk

24 wk

RegimenLDV/SOF

LDV/SOF + RBV

Duration/±

RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

Results: SVR12 by Treatment Regimen

Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone


98%

97%

99%

96%

99%

96%

98%

97%

100%

Treatment Naïve

95%

94%

98%

95%

96%

90%

96%

98%

100%

Treatment Experienced

Overall SVR12

Duration

12 wk

24 wk

Regimen

LDV/SOF

LDV/SOF + RBV

Duration/±

RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

98%

97%

99%

96%

99%

96%

98%

97%

100%

Treatment Naïve

95%

94%

98%

95%

96%

90%

96%

98%

100%


Overall SVR12

Duration12 wk

24 wk

RegimenLDV/SOF

LDV/SOF + RBV

Duration/±

RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

Results: SVR12 by Treatment Regimen

Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone


98%

97%

99%

96%

99%

96%

98%

97%

100%

Treatment Naïve

95%

94%

98%

95%

96%

90%

96%

98%

100%


Overall SVR12

Duration

12 wk

24 wk

RegimenLDV/SOF

LDV/SOF + RBV

Duration/±

RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

98%

97%

99%

96%

99%

96%

98%

97%

100%

Treatment Naïve

95%

94%

98%

95%

96%

90%

96%

98%

100%


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TURQUOISE-II: GT1 treatment-naive and

experienced cirrhotic patients

• ABT-450/r/ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV for 12 or 24 weeks

• ABT-450/r/ombitasvir = 150/100 mg/25 mg QD co-formulated;• dasabuvir = 250 mg BID; RBV = weight-based BID. • Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869.

ABT-450/r /ombitasvir + dasabuvir + RBV

0 2412

Study weeks

n=208

n=172ABT-450/r /ombitasvir + dasabuvir + RBV

HCV GT1, treatment-naive or -experienced,

cirrhotic(N=380)

TURQUOISE-II: GT1 treatment-naive and experienced

cirrhotic patients – baseline characteristics

• Poordad F, et al. N Engl J Med 2014. Online DOI:10.1056/NEJMoa1402869.

12-Week Arm

(N=208)

24-Week Arm

(N=172)

Male (%) 70.2 70.3

White race (%) 95.7 93.6

Hispanic or Latino ethnicity (%) 12.0 11.6

Mean age (years) 57.1 56.5

Mean BMI (kg/m2) 27.9 27.9

IL28B non-CC (%) 83.2 80.2

HCV genotype 1a (%) 67.3 70.3

Treatment-naïve (%) 41.3 43.0

Treatment-experienced (%) 58.7 57.0

Relapse 13.9 13.4

Partial responder 8.7 7.6

Null responder 36.1 36.0

Platelet count <100 x 109/L (%) 21.6 19.2

Serum albumin <3.5 g/dL (%) 12.0 10.5

Child-Pugh score >5 (%) 18.3 18.6

3D + RBV

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TURQUOISE-II: GT1 treatment-naive and experienced

cirrhotic patients – baseline characteristics


12-Week Arm

(N=208)

24-Week Arm

(N=172)

Male (%) 70.2 70.3

White race (%) 95.7 93.6

Hispanic or Latino ethnicity (%) 12.0 11.6

Mean age (years) 57.1 56.5

Mean BMI (kg/m2) 27.9 27.9

IL28B non-CC (%) 83.2 80.2

HCV genotype 1a (%) 67.3 70.3

Treatment-naïve (%) 41.3 43.0

Treatment-experienced (%) 58.7 57.0

Relapse 13.9 13.4

Partial responder 8.7 7.6

Null responder 36.1 36.0

Platelet count <100 x 109/L (%) 21.6 19.2

Serum albumin <3.5 g/dL (%) 12.0 10.5

Child-Pugh score >5 (%) 18.3 18.6

3D + RBV

TURQUOISE-II: SVR12 rates in GT1 treatment-naive and

experienced cirrhotic patients


0

20

40

60

80

100

SV

R1

2,

% P

ati

en

ts

12 Weeks3D + RBV

91.8

191208

95.9

165172

24 Weeks3D + RBV

P=0.089

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TURQUOISE-II: SVR12 rates in GT1 treatment-naive and

experienced cirrhotic patients by HCV genotype


0

20

40

60

80

10088.6

12-week arm

24-week arm

98.594.2 100

GT1a GT1b

3D + RBV

SV

R1

2,

% P

ati

en

ts

124140

6768

114121

5151

TURQUOISE-II: SVR12 rates in GT1a treatment-naive and

experienced cirrhotic patients by prior treatment response


0

20

40

60

80

10092.2

12-week arm

24-week arm

92.9

Naive Prior RelapseResponse

3D + RBV

SV

R1

2,

% P

ati

en

ts

5964

1415

5256

1313

93.3 100 100 100 80.0 92.9

1111

4050

1010

3942

Prior PartialResponse

Prior NullResponse

HCV Subtype 1a

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TURQUOISE-II: SVR12 rates in GT1b treatment-naive and

experienced cirrhotic patients by prior treatment response


0

20

40

60

80

100100

12-week arm

24-week arm

100

Naive Prior RelapseResponse

3D + RBV

SV

R1

2,

% P

ati

en

ts

2222

2525

1818

2020

100 100 85.7 100 100 100

67

1414

33

1010

Prior PartialResponse

Prior NullResponse

HCV Subtype 1b

TURQUOISE-II: safety summary in GT1 treatment-naive

and experienced cirrhotic patients


Hepatic decompensation events were rare (4 patients, 1.1%)

• None were considered related to study drug

Event, %

12-Week Arm

(N=208)

24-Week Arm

(N=172)

Any AE 91.8 90.7

Severe AE 6.7 7.6

Serious AE 6.3 4.7

AE leading to drug discontinuation 1.9 2.3

Death* 0 0

3D + RBV

*1 patient with a non-treatment emergent death (occurring 80 days after last dose of study treatment), not attributed to 3D or RBV.

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TURQUOISE-II: laboratory assessments in GT1 treatment-naive

and experienced cirrhotic patients


ALT elevation

• Asymptomatic, transient, and improved or resolved with ongoing study drug dosing

Bilirubin elevation

• Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia

Hemoglobin decrease

• Managed with reduction of ribavirin dose in 34 patients (8.9%)

12-Week Arm

(N=208)

24-Week Arm

(N=172)

ALT >5x ULN (%) 2.9 0

Total bilirubin >3x ULN (%) 13.5 5.2

Hemoglobin (%)

<10 g/dL 7.2 11.0

<8.0 g/dL 1.4 0.6

3D + RBV

LDV/SOF + RBV for HCV Patients with

Decompensated Cirrhosis

• 108 patients randomized 1:1 to 12 or 24 weeks of treatment

• Stratified by CTP class B [7-9] or C [score 10–12]*

• Broad inclusion criteria:

– No history of major organ transplant, including liver

– No hepatocellular carcinoma (HCC)

– Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL

– CrCl≥ 40 mL/min, Platelets > 30,000

• RBV dosing: dose escalation, 600–1200 mg/d

Prospective, multicenter study of 12 or 24 weeks of LDV/SOF + RBV in TN and TE HCV GT 1 and 4 patients with CTP B (N=59) or CTP C (N=49) clinically decompensated cirrhosis

Wk 0 Wk 12 Wk 36Wk 24

SVR12N=53

SVR12N=55 LDV/SOF + RBV

LDV/SOF + RBV

*Patients with CTP scores 13-15 were excludedFlamm, AASLD, 2014, Oral #239

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Demographics• SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

CTP B CTP C

12 Weeks

n=30

24 Weeks

n=29

12 Weeks

n=23

24 Weeks

n=26

Median age, y (range) 60 (28-69) 58 (35-69) 58 (41-71) 59 (48-68)

Male, n (%) 22 (73) 18 (62) 14 (61) 18 (69)

White, n (%) 29 (97) 26 (90) 21 (91) 24 (92)

BMI ≥30 kg/m2, n (%) 10 (33) 10 (34) 13 (57) 9 (35)

Mean HCV RNA, log10

IU/mL (range) 5.9

(4.3-6.7)

5.8

(3.2-7.1)

5.6

(4.1-6.5)

5.8

(3.7-6.9)

GT 1a, n (%) 19 (63) 22 (76) 15 (65) 18 (69)

IL28B non-CC, n (%) 26 (87) 23/28 (82) 17 (74) 19 (73)

Prior HCV treatment, n (%) 22 (73) 19 (66) 11 (48) 18 (69)

MELD score, n (%)

<10 6 (20) 8 (28) 0 0

10‒15 21 (70) 16 (55) 16 (70) 13 (50)

16-20 3 (10) 5 (17) 7 (30) 12 (46)

21-25 0 0 0 1 (4)

Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)

Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)Flamm, AASLD, 2014, Oral #239

Demographics• SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

CTP B CTP C

12 Weeks

n=30

24 Weeks

n=29

12 Weeks

n=23

24 Weeks

n=26

Median age, y (range) 60 (28-69) 58 (35-69) 58 (41-71) 59 (48-68)

Male, n (%) 22 (73) 18 (62) 14 (61) 18 (69)

White, n (%) 29 (97) 26 (90) 21 (91) 24 (92)

BMI ≥30 kg/m2, n (%) 10 (33) 10 (34) 13 (57) 9 (35)

Mean HCV RNA, log10

IU/mL (range) 5.9

(4.3-6.7)

5.8

(3.2-7.1)

5.6

(4.1-6.5)

5.8

(3.7-6.9)

GT 1a, n (%) 19 (63) 22 (76) 15 (65) 18 (69)

IL28B non-CC, n (%) 26 (87) 23/28 (82) 17 (74) 19 (73)

Prior HCV treatment, n (%) 22 (73) 19 (66) 11 (48) 18 (69)

MELD score, n (%)

<10 6 (20) 8 (28) 0 0

10‒15 21 (70) 16 (55) 16 (70) 13 (50)

16-20 3 (10) 5 (17) 7 (30) 12 (46)

21-25 0 0 0 1 (4)

Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)

Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)Flamm, AASLD, 2014, Oral #239

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Results: SVR12

CTP B CTP C

SV

R1

2 (

%)

26/30 19/22 18/2024/27

Error bars represent 90% confidence intervals.

LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV

Flamm, AASLD, 2014, Oral #239

MELD Scores Change From Baseline to

Follow-Up Week 4

46

n=5 n=5 n=2 n=3

(-8)

(+10)

CPT B CPT C

12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

*Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.

Flamm, AASLD, 2014, Oral #239

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Solar 1

• The Lazarus Trial

• Persuades me to treat decompensated

cirrhosis

The UK EAP

• Patients with decompensated cirrhosis offered

sofosbuvir + ledipasvir or daclatasvir + RBV

• Over 700 patients on therapy to-date

• Early results from first 250 patients – 8

relapsers

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End stage liver disease

• We will see more and more patients with

advanced liver disease

• We need to monitor

• Medication

• Portal Pressure

• HCC

• We need to treat with interferon free regime

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professor graham foster · 12/12/2014 1 in partnership with queen mary, university of london, uk...

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