The next generation of Treatment for Hepatitis CHepatitis C

Treatment of CHC: OutcomesTreatment of CHC: Outcomes

Goal of therapy is to render the patient PCR Goal of therapy is to render the patient PCR negative for HCV RNAnegative for HCV RNA

Need to remain PCR negative 6 months Need to remain PCR negative 6 months after end of therapyafter end of therapy

Response rates for combination therapyResponse rates for combination therapyGenotype 1 up to 40%Genotype 1 up to 40%Genotypes 2 or 3 up to 80%Genotypes 2 or 3 up to 80%

Evolution of HCV genotype 1 treatment

1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55

5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon

DAA: direct-acting antiviralSVR: sustained virologic response

SV

R r

ate

(%

)

2–7%

IFN1

16–28%

IFN +

RBV1

20

40

60

80

100

1990 2000 2010 2020

Treatment Issues

• Genotypes 2/3 – nothing new on horizon

• Genotype 1 – failure rate 50-60%

• No good options for treatment failures

New treatment for Genotype 1 HCV

(Rx naïve patients)

Direct Acting Anivirals (DAAs)

• DAA-based triple combination therapy led to improved SVR rates over current therapy in Phase II trials – 61–85% SVR with telaprevir-based therapy4–6

– 54–75% SVR with boceprevir-based therapy7

• Telaprevir and boceprevir have recently completed Phase III trials in treatment-naïve patients– Telaprevir: ADVANCE8 and ILLUMINATE9

– Boceprevir: SPRINT-210

ADVANCE (telaprevir): study design (N=1088)

240 48 72Weeks

128 36

T12PR(N=363) TVR + PR

Follow-upSVR

PR

eRVR+eRVR+Follow-up

SVR

PR

Follow-up

SVR

TVR + PR

T8PR(N=364)

PR

Pbo +

PR

Follow-upSVReRVR+eRVR+

PR

Follow-up

Follow-up

eRVR–eRVR–

eRVR–eRVR–

Follow-upPR48

(control)(N=361)

SVR

Pbo + PR PR

Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: extended rapid virologic response (undetectable HCV RNA at Weeks 4 and 12); Pbo: placebo; PR: peginterferon/ribavirin; TVR: telaprevir

Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: extended rapid virologic response (undetectable HCV RNA at Weeks 4 and 12); Pbo: placebo; PR: peginterferon/ribavirin; TVR: telaprevir Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

SPRINT-2 (boceprevir): study design (N=1097)

Follow-upSVR

Follow-upSVR

Follow-upSVR

PR + Boceprevir

PR + Boceprevir

PRlead-in PR + Placebo

PR48 ControlN=363

BOCRGT

N=368

BOC44/PR48N=366

Weeks 8–24 HCV RNA undetectable

Weeks 8–24 HCV RNA detectable*

PRlead-in

PRlead-in

PR + Placebo

0 48 72Weeks

284 8

Follow-upSVR

24

*But with undetectable HCV RNA at Week 24Peg-IFN alfa-2b dose: 1.5 µg/kg/weekRBV dose: 600–1400 mg/day in a divided daily doseRGT: response-guided therapy

*But with undetectable HCV RNA at Week 24Peg-IFN alfa-2b dose: 1.5 µg/kg/weekRBV dose: 600–1400 mg/day in a divided daily doseRGT: response-guided therapy Poordad F, et al. Hepatology 2010;52(Suppl.):402A

ILLUMINATE (telaprevir): study design (N=540)

Follow-up

SVR

Follow-up

SVR

PR

PR

Randomized Treatments

0 1220

Follow-up

SVR

PR

Assigned Treatment

eRVR–eRVR–

eRVR+eRVR+ Non-inferiority (NI)Non-inferiority (NI)

Follow-up

72 weeks

20 24 36 48 60 72

T12PR PR

eRVR+T12PR24N=162

eRVR+T12PR48N=160

eRVR–T12PR48N=118

Weeks

Sherman KE, et al. Hepatology 2010;52(Suppl.):401A

Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100)Stopping rules were similar to ADVANCE

ADVANCE and ILLUMINATE: SVR rates with telaprevir-based therapy versus PR alone

T12PR

659/903

T12PR

659/903

PR48

158/361

PR48

158/361

72–75*

Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; Sherman KE, et al. CROI 2011. Abstract 957*p<0.0001 vs PR48 in ADVANCE (75% versus 44%)

SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone

BOC RGT

233/368

BOC RGT

233/368

BOC44/PR48

242/366

BOC44/PR48

242/366

PR48

137/363

PR48

137/363

Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402AFor non-Black patients, p<0.0001 for both boceprevir arms versus PR48; for Black patients, p=0.044 and p=0.004 for BOC RGT and BOC44/PR48, respectively, versus PR48

Tripple therapy works in advanced fibrosisADVANCE (telaprevir): SVR rates by fibrosis stage

SV

R (

%)

PR48

134/288n/N=

ADVANCE1

1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A;

T12PR

226/290

PR48

24/73

T12PR

45/73

No, minimal or portal fibrosis

Bridging fibrosis or cirrhosis

Tripple therapy works in all IL28B genotypesADVANCE (telaprevir): SVR rates by IL28B genotype

Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

SV

R (

%)

PR48

35/55n/N=

CC TT

T12PR

45/50

PR48

6/26

T12PR

16/22

PR48

20/80

T12PR

48/68

CT

Samples were available for 454/1088 (42%) patients enrolled in ADVANCE

Safety and tolerability with DAAs

• Common AEs with PR include:1–3

– Fatigue, headache, nausea, pyrexia and myalgia– Anemia and neutropenia– Depression, irritability and insomnia– Rash

• Additional management considerations with DAAs – Telaprevir:4–6 rash, anemia– Boceprevir:7,8 anemia and dysgeusia

1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):147. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Bacon BR, et al. Hepatology 2010;52(Suppl.):430A AE: adverse event

Evolution of HCV genotype 1 treatment

1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55

5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon

DAA: direct-acting antiviralSVR: sustained virologic response

SV

R r

ate

(%

)

2–7%

IFN1

16–28%

IFN +

RBV1

20

40

60

80

100

1990 2000 2010 2020

What about Genotype 1 patients

with previous treatment failure?

Definitions of failure on prior Peg-IFN/RBV therapy

Detection limit

Relapse

Null response

Partial response

Treatment

HC

V R

NA

leve

l

2 log10 drop

Non-response

Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22

REALIZE (telaprevir): SVR in prior relapsers, partial responders and null responders

PR48

4/27

T12/PR48

29/49

SV

R (

%)

Prior relapsers Prior partialresponders

LI T12/PR48

26/48n/N=

PR48

2/37

T12/PR48

21/72

LI T12/PR48

25/75

PR48

16/68

T12/PR48

121/145

LI T12/PR48

124/141

Prior null responders

**

**

**

Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14*p<0.001 vs PR48; post-hoc analysis

RESPOND-2 (boceprevir): SVR in prior relapsers and partial responders

PR48

2/29

BOC44/PR48

30/58

SV

R (

%)

Prior relapsers Prior partialresponders

BOCRGT

23/57n/N=

PR48

15/51

BOC44/PR48

77/103

BOC RGT

72/105

Prior null responders were excluded from RESPOND-2

Bacon BR, et al. Hepatology 2010;52(Suppl.):430A

Summary of Tripple therapy with DAAs

• Only for Genotype 1 Hepatitis C

• Uses Peg Inf + Ribavirin + DDA

• Improved response in naïve patients (65-75%)

• Improved response in prior non-responders

• Improved response in difficult to treat groups

COSTCOSTCost of treatmentCost of treatment

genotype 1 genotype 1 £12,782 for 48 weeks treatment£12,782 for 48 weeks treatmentgenotype 2 or 3 genotype 2 or 3 £5,233 for 24 weeks £5,233 for 24 weeks

Supportive therapy with:Supportive therapy with:Epoetin - Epoetin - 8000 units twice weekly = £3,216 for 6 months8000 units twice weekly = £3,216 for 6 months

G-CSF - G-CSF - Neupogen 30million units/wk = £1752 for 6 monthsNeupogen 30million units/wk = £1752 for 6 months

Cost of addition of DAA £14,000 - £24,000Cost of addition of DAA £14,000 - £24,000To be confirmed Sept 2011

Who will get the new drugs?