Response Guided Therapy

Fabien ZoulimHepatology Department & INSERM Unit 1052,

Lyon UniversityLyon, France

Rationale for response guided therapy (RGT) ?

• Potent and rapid viral suppression in patients receiving DAA based therapy

• Can the duration of treatment be shortened in genotype 1-infected patients receiving DAA-based therapy?

• Is the situation the same for naïve and treatment experienced patients ?

Early viral load decline through Week 12 of telaprevir-based regimens

Non-responders to prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=130)

Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=83)

Null responders and partial responders to prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=79)

Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=28)

Treatment-naïve patients who received T12/PR in PROVE1 or PROVE2 (n=338)

1280 1 2 3 40

–1

–2

–4

–3

–5

–6

–7

Med

ian

chan

ge fr

om b

asel

ine

(log 10

HCV

RN

A)Time (weeks)

Poordad F, et al. J Hepatol 2010; 52(Suppl. 1):S121–S122

Kinetics of response to Boceprevir based therapy (Sprint-2 & Respond 2)

Respond-2Sprint-2

RGT (PR4/BOC-PR32/PR12) RVS n/N (%)

PR4/BOC-PR44 RVS n/N (%)

Respond-2 Late Responder 27/34 (79) 29/40 (73)

Meeting FDA 27-28 avril 2011

Can the duration of treatment be shortened in treatment-naïve, genotype 1-infected patients receiving DAA-based

therapy?

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

240 48 72Weeks

128 36

T12PR(n=363) TVR + PR

Follow-upSVR

PR

eRVR+Follow-up

SVR

PR

Follow-up

SVR

TVR + PR

T8PR(n=364)

PR

Pbo +

PR

Follow-upSVReRVR+

PR Follow-up

Follow-up

eRVR–

eRVR–

Follow-upPR48

(control)(n=361)

SVRPbo + PR PR

Jacobson IM, et al. N Engl J Med 2011;364:2405–16Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: undetectable HCV RNA at Week 4 and 12

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

Follow-up

SVR

Follow-upSVR

PR

PR

Randomized Treatments

0 1220

Follow-upSVR

PR

Assigned TreatmenteRVR–

eRVR+ Non-inferiority (NI)

Follow-up

72 weeks

20 24 36 48 6072

T12PR PR

eRVR+T12PR24n=162

eRVR+T12PR48n=160

eRVR–T12PR48n=118

Weeks

Sherman KE, et al. N Engl J Med 2011;365:1014–24

Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100)Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: undetectable HCV RNA at Week 4 and 12

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

Follow-upSVR

Follow-upSVR

Follow-upSVR

PR + BOC

PRlead-in PR + Pbo

PR48 Controln=363

BOCRGT

n=368

BOC44/PR48n=366

Weeks 8–24 HCV RNA undetectable

HCV RNA detectable at any time from Week 8 onwards, but Week 24 undetectable

PRlead-in

PRlead-in

PR + Pbo

0 48 72Weeks

284 8

Follow-upSVR

24

Peg-IFN alfa-2b dose: 1.5 µg/kg/weekRBV dose: 600–1400 mg/day in a divided daily dose Poordad F, et al. N Engl J Med 2011;364:1195–206

PR + BOC

ADVANCE and ILLUMINATE (telaprevir): undetectable HCV RNA at Weeks 4 and 12

Series10

20

40

60

80

100

9

70

8

63

Patie

nts

with

und

etec

tabl

e H

CV R

NA

(%)

Week 4 (RVR) Weeks 4 and 12 (eRVR)

Patients eligible to receive 24 weeks

of treatment in total

PR48

34/361

T12PR

635/903

T12PR

565/903

PR48

29/361n/N=

Adapted from Sherman KE, et al. CROI 2011. Abstract 957

ILLUMINATE (telaprevir): SVR rates by treatment duration in patients treated with T12PR (N=540)

Treatment duration according to eRVR status

60%*n=32222%

n=118

Sherman KE, et al. N Engl J Med 2011;365:1014–24

0

20

40

60

80

100 9288

64

23SV

R (%

)

<20 weeks

23/100

SVR rate

18%n=100

Eligible for 24 weeks and randomized to 24 or 48 weeks*

48 weeks

<20 weeks (due to premature treatment discontinuation)

*Patients who achieved eRVR (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone65% of patients achieved an eRVR (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20

eRVR+*

eRVR–

<20 weeks

eRVR– T12PR48

76/118

eRVR+ T12PR48

140/160

eRVR+ T12PR24

149/162

4.5% (2-sided 95% CI = –2.1% to +11.1%)

SPRINT-2 (boceprevir): undetectable HCV RNA at Week 8 and Weeks 8 to 24

Series10

20

40

60

80

100

17

57 56

12

44 44

Patie

nts

with

und

etec

tabl

e H

CV R

NA

(%)

PR48

60/363

BOC44/PR48

204/366n/N=

Week 8 Weeks 8 to 24

BOC RGT

208/368

BOC44/PR48

161/366

BOC RGT

162/368

Patients eligible to receive 28 weeks of total treatment

Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206

PR48

43/363

SPRINT-2 (boceprevir): SVR rates and treatment duration in BOC arms

0

20

40

60

80

100 96

72

15

96

75

SVR

(%)

<28 wks18/124

–

48 wks59/82

SVR ratesTreatment duration in RGT arm

28 weeks if undetectable HCV RNA from Weeks 8–24

48 weeks if detectable HCV RNA at least once between Weeks 8–24 but undetectable at Week 24

<28 weeks (discontinued because of detectable HCV RNA at Week 24, adverse events or non-medical reasons)

+

28 wks156/162

44%n=162

34%n=124

22%n=82

<28 weeks 28 weeks

48 weeks

Poordad F, et al. N Engl J Med 2011;364:1195–206 Bronowicki J-P, et al. Hepatology 2010;52(Suppl.):881A

+

48 wks155/161

–

48 wks55/73

Undetectable Weeks 8–24

BOC RGT BOC44/PR48

Shorter duration of therapy is possible in naive patients who achieve an eRVR

Can the duration of treatment be shortened in treatment-experienced,

genotype 1-infected patients receiving DAA-based therapy?

REALIZE (telaprevir): study design (N=662)

484 160 128Weeks

72

T12/PR48 Peg-IFN + RBVTVR + Peg-IFN + RBV

Pbo + Peg-IFN +

RBV n=266Follow-up

SVR assessment

TVR + Peg-IFN + RBV Peg-IFN + RBV

LI T12/PR48n=264

Follow-upPbo +

Peg-IFN + RBV

PR48 (control) Pbo + Peg-IFN + RBV Peg-IFN + RBV

n=132Follow-up

Zeuzem S, et al. N Engl J Med 2011;364:2417–28

Randomization was stratified by viral load and prior response category. Stopping rules applied for telaprevir (Weeks 4, 6, and 8 after telaprevir start) and PR (Weeks 12/16 [depending on treatment arm], 24, and 36)Peg-IFN alfa-2a: 180μg/week subcutaneously; RBV: 1000–1200mg/day; TVR: 750mg every 8 hours

RESPOND-2 (boceprevir): study design (N=403)

484 160 128Weeks

72SVR assessment

Pbo + Peg-IFN + RBVPR48

(control)n=80

Follow-upPeg-IFN + RBV

BOC + Peg-IFN + RBVBOC44/

PR48n=161

Follow-upPeg-IFN + RBV

36

Pbo + Peg-IFN + RBV Follow-up

Week 8 detectable HCV RNA +Week 12 undetectable HCV RNA

Follow-up

Week 8 and 12 undetectable HCV RNA

Patients with detectable HCV RNA at Week 12 were considered treatment failures and discontinued treatmentPeg-IFN alfa-2b: 1.5μg/kg/week; RBV: 600–1400mg/day; BOC: 800mg q7–9h Bacon BR, et al. N Engl J Med 2011;364:1207–17

BOC + Peg-IFN + RBV BOCRGT

n=162

Peg-IFN + RBV

Series10

20

40

60

80

10089

100

21

Telaprevir: SVR in prior relapsers eligible to receive 24 weeks of therapy

SVR

(%)

n/N =

Study 106T12/PR24

25/28

Study 107T12/PR24

24/24

INCIVO (telaprevir) EU SmPCPatients with undetectable HCV RNA at Weeks 4 and 12 of subsequent telaprevir-based treatment

Series10

20

40

60

80

100100

86 88

12

40 43

PR48

7/7

BOC44/PR48

74/84

SVR

(%)

Undetectable HCV RNA at treatment week 8

Detectable HCV RNA at treatment week 8

BOC RGT

64/74n/N=

PR48

8/65

BOC44/PR48

30/70

BOC RGT

29/72

22

RESPOND-2 (boceprevir): SVR by Week 8 HCV RNA levels*

Bacon BR, et al. N Engl J Med 2011;364:1207–17; Bacon BR, et al. Hepatology 2010;52(Suppl.):430A

Overall, 46% of patients eligible to receive 36 weeks of total treatment

*Some patients had missing values at Week 8

Shorter duration of therapy is possible in relapsers/partial responders who achieve an

eRVR during DAA based triple therapy

Response Guided Therapy

Can be applied to: • Naive patients without cirrhosis• Relapsers • Partial responders

Cannot be applied to: • Cirrhotics• Null responders• Blacks• IL28