Treatment of Hepatitis C in patients with thalassaemia. Where are we now?

• Telaprevir and boceprevir harbingers of important treatment advance

• Improved response rates observed : – naive and experienced patients

• SVR > 70% have been reported– in genotype 1 infection

• Efficacy in the treatment of genotype 2-6 has not been fully tested.

The natural history of fibrosis in chronic viral hepatitis

F0 F2 F3 F4

Courtesy Pierre Bedossa

Telaprevir ADVANCE: SVR in naïve patients

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t o

f p

atie

nts

w

ith

HC

V R

NA

Un

det

ecta

ble

SVR

7569

44

T12PR T8PR PR

P<0.0001

P<0.0001

271/363 250/364 158/361n/N =

Jacobson IM, et al. N Engl J Med 2011;364:2405-16; 2.

Evidence for efficacy: boceprevir in treatment-naïve, genotype 1 patients (SPRINT-2)

0

20

40

60

80

100

38

63 66

SV

R (

%)

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363n/N =

Boceprevir EU SmPC

* *

*p<0.001 for both boceprevir arms versus PR48SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward

The first generation protease inhibitors. Where are we now?

• Response rates in patients with cirrhosis improved but suboptimal

• Naïve patients without severe fibrosis – respond better

• Prior null response and cirrhosis less likely to respond to retreatment

• Inherited IL28b haplotypes continue to influence response rates

• Response rates lower in subtype 1a vs 1b. • Side effects testing for patients

REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV

SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Pol S, et al. Hepatology 2011;54(Suppl. S1):374A

Series10

20

40

60

80

100

32

137

18

0

20

60

10

87 85 8477

56

3441 42

14

53/62n/N= 2/1512/38 145/167 10/180/53/17 36/47 16/380/91/5 11/32

No, minimal or portal fibrosis

CirrhosisStage

Pbo/PR48

Pooled T12/PR48

SV

R (

%)

48/571/15 1/18 24/59 1/10 7/50

Bridgingfibrosis

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

Prior relapsers

Prior partial responders

Prior null responders

The paradox of progress

• Advances have brought higher rates of cure – but more complexity to treatment of hepatitis C- a

paradox of progress– Do not make treatment more straightforward– Complex process of decision making is required to

assess • Side effects?• Resistance in patients who fail treatment

Managing adverse events:

– Rashes• varying grades of severity and duration have been

reported in 55% telaprevir• Most drug related dermatitis moderate severity• Unpredictably progress• 5 % of patients experienced severe rash• Drug Rash with Eosinophilia and Systemic Symptoms

(DRESS) occurred in 0.4% and Stevens-Johnson syndrome in 0.1% in clinical trials.

– Anaemia• Particular relevance in patients with thalassaemia

Still stuck with IFN

• The requisite backbone of PEG IFN:– other problems associated with PEG IFN and RBV

use• Including depression, psychiatric symptoms worsening

of liver function and severe infections

– render a large group intolerant of PEG IFN ineligible for treatment.

GS-7977 + PR12 wk

GS-7977 + PR24 wk

GS-7977 + PR12 + 12 wk

0

25

50

75

100 9498 9798 99 99

94 92 9290

Wk 4EOTSVR4SVR12P

atie

nts

(%)

SVR12 not yet reported for the 24 week groups

ATOMIC study: GS7977 + IFN + RBV 12 weeksInterferon sparing: a new threshold

Kowdley KV, et al. EASL 2012, Barcelona, #1

BMS-790052 + BMS-650032: AI447011

In null-responders, BMS-790052 + BMS-650032 appear to require PegIFN/RBV to prevent breakthrough and the occurrence of resistance

BMS-790052 + BMS-650032

Lok A, et al NEJM

Lo

g 10 H

CV

RN

A

7

6

5

4

3

2

1

Week

0 1 2 3 4 6 8 10 12

*

LOQ 25 IU/mLLOD <10 IU/mL

LOD

LOQ

LOD

LOQ

Lo

g 10 H

CV

RN

A

7

6

5

4

3

2

1

Week

0 1 2 3 4 6 8 10 12

initiation of PegIFN/RBV

BMS-790052 + BMS-650032 + PR

Quadruple regimen

Quad versus DAA combination

(NS5a inhibitor and Protease inhibitor)

ASPIRE (TMC435): SVR24 by prior response and Metavir score

Pat

ien

ts w

ith

SV

R24

(%

)

TMC435100mg*PR48

48 29 10

TMC435150mg*

PR48

52 26 15

TMC435100mg* PR48

30 20 11

TMC435150mg*PR48

48 21 11

TMC435100mg*PR48

38 29 13

PR48

16 10 6

PR48

12 10 2

PR48

13 3 2

TMC435150mg* PR48

29 21 13

Relapsers Partial responders Null responders

Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1

n=

*All TMC435 duration pooled

Will we have better, more tolerable interferons?

Lambda interferonNo haematological toxicity

Daclatasvir and GS-7977 across HCV genotypes 1–3

Sulkowski M, et al. EASL 2012, Barcelona, #1422

Wk 4 Wk 24 (EOT) f/u(SVR4)

0

25

50

75

100

88 93 8879 93 10064 86 79

Group B Group D Group F

Wk 4 Wk 24 (EOT) f/u(SVR4)

0

25

50

75

100

87 87 10093 86 10073 93 100

Group A Group C Group E

Pa

tien

ts a

chie

vin

g e

nd

po

int (

%)

100 100 100 100 100 10087 86 93 100 100 100 94 100 86 88 100 86

%<LOD

%<LLOQ

G1a/b G2/3mITT*

*Bars <100% after 4 weeks reflect missing values

All oral regimens: a realistic dream?

• Therapeutic landscape is undoubtedly forever changed for the better

• High barrier to resistance and pan-genotypic effects. • Do not yet know whether RBV remains important, or

the appropriate dose of RBV in these regimens• Null responders to PEG IFN and RBV are null

responders to both agents?• Multiple DAAs without RBV? • Costs will escalate

DAA + IFN (IFN freer) or IFN free?

Treatment: next wave

DAA + PEG IFN RBV TMC 435 + PEG IFN RBV 7977 + PEG IFN RBV Daclatisvir + PEG IFN RBV Asunaprevir + PEG IFN RBV BI 1201335 + PEG IFN RBV MK5172 + PEG IFN RBV

DAA + DAA + (DAA, R)

Quadruple therapy

12 weeks