Telaprevir: Phase 3 Trials in Treatment-Naïve Patients

Paris, France 30 January, 2012

Ira M. Jacobson, M.D.

Vincent Astor Professor of Medicine

Chief, Division of Gastronterology and Hepatology

Medical Director, Center for the Study of Hepatitis C

Weill Cornell Medical College

The Evolution of HCV Therapy

Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39:1147-1171.

0

20

40

60

80

100

0

20

40

60

80

100

SV

R

(%)

IFN6 mo

IFN/RBV6 mo

PEG-IFN /RBV12 mo

IFN12 mo

IFN/RBV12 mo

PEG-IFN12 mo

1986 1998 2001 2002

66

1616

34344242 3939

54-5654-56

Abbreviations: ARFP, alternate reading frame protein; IRES, internal ribosome entry site; UTR, untranslated region. Glenn JS. Clin Liver Dis. 2005;9:353-369.

Core E1 E2 P7

NS2 NS3 NS4A

NS4B NS5A NS5B

ARFP

UTR

IRES

55 33(U/UC)

UTR

ProteaseHelicaseProteaseHelicase PolymerasePolymerase

StructuralStructural NonstructuralNonstructural

Hepatitis C Virus GenomeThe Function of the NS3/4A Serine Protease

EnvelopeEnvelope

Phase 1 Trial of Telaprevir vs PEG IFNvs PEG IFN Alone

Kieffer T, et al. Hepatology. 2007;46:631-639

-6-6

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414

Study Time (days)Study Time (days)

HC

V R

NA

Ch

ang

e fr

om

Bas

elin

e H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

g(L

og

1010 I

U/m

L)

IU

/mL

)

Telaprevir + Telaprevir + PEG IFN alfa-2a N=8PEG IFN alfa-2a N=8

Telaprevir N=8Telaprevir N=8

PEG IFN alfa-2a PEG IFN alfa-2a + placebo + placebo N=4N=4

Baseline Baseline

Sequence analysis

1515

•Resistant mutations emerged within 4-7 days; subsequently suppressed by PEG IFN + RBV•Differences in G1 subtypes

Lessons Learned From Phase 2 Trials With Telaprevir + PR in Naïve Patients

(PROVE1, PROVE2)

Higher rates of RVR, lower rates of relapse drive higher rates of SVR in G1

Foundation for exploration of response guided therapy in phase 3

12 weeks triple therapy too short to achieve optimal results in overall population

Inability to delete ribavirin from regimen Side effect profile

McHutchison J et al NEJM 2009;Hezode C et al NEJM 2009

Phase 3 Trials of Telaprevir in Treatment-Naïve Patients

ADVANCEPivotalN=1088

ILLUMINATESupportive

N=540

ADVANCE: Treatment Naïve G1

(T) TVR = telaprevir 750 mg q8h; Pbo = Placebo; (P) Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV = ribavirin 1,000 or 1,200 mg/da(T) TVR = telaprevir 750 mg q8h; Pbo = Placebo; (P) Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV = ribavirin 1,000 or 1,200 mg/da

eRVR = HCV RNA undetectable at week 4 and week 12 (Taqman v2.0)

240 48 72Weeks 128 36

Follow-upPR48 (control)

SVRPbo + PR PR

T12PR TVR + PR

Follow-upSVR

eRVR- PR .

eRVR + eRVR + Follow-up

SVR

PR

Follow-upSVR

TVR + PR

T8PR

eRVR- PR .

Pbo +PR

Follow-upSVReRVR +eRVR +

PR

72 weeks72 weeks

Follow-up

Follow-up

Randomized, Double-Blind, Placebo-Controlled for Telaprevir

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

ADVANCE: Stopping Rules

Timepoint Criteria for Stopping Action

Week 4* HCV RNA >1000 IU/mLDiscontinue TVR, continue PR

Week 12 HCV RNA <2 log10 decline Discontinue all treatment

Week 24-40 HCV RNA detectableDiscontinue all treatment

*Applied to telaprevir-treated patients only*Applied to telaprevir-treated patients only

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

ADVANCE: SVR Rates

SVRSVR

75756969

4444

P<0.0001

P<0.0001

271/363271/363 250/364250/364 158/361158/361n/N =n/N =

Per

cent

of

patie

nts

with

SV

RP

erce

nt o

f pa

tient

s w

ith S

VR

0

10

20

30

40

50

60

70

80

90

100

T12PRT12PR T8PRT8PR PRPR

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

Higher SVR Rates From ADVANCE in FDA Approved Label

SVR rates in package insert (%) Explanations for change

7972

46

Counted HCV RNA between LLQ and LLD at f/u week 24

as SVR

Counted SVR12 as SVR

ADVANCE: Relapse Rates

27/31427/314 28/29528/295 64/22964/229 51/18951/18918/24718/24717/26417/264

99 99

2828

66 77

2727

Per

cent

of

patie

nts

with

rel

apse

Per

cent

of

patie

nts

with

rel

apse

OverallOverall Completed RegimenCompleted Regimenn/N =n/N =

Overall – patients who had undetectable HCV RNA at the last dose of treatment Completed regimen – patients who completed assigned regimen and had undetectable HCV RNA after the last dose of treatment

Overall – patients who had undetectable HCV RNA at the last dose of treatment Completed regimen – patients who completed assigned regimen and had undetectable HCV RNA after the last dose of treatment

0

10

20

30

40

50

60

70

80

90

100 T12PRT12PR T8PRT8PR PRPR

ADVANCE: RVR and eRVR Rates

246/363246/363 242/364242/364 34/36134/361 29/36129/361207/364207/364212/363212/363

6868 6666

99

5858 5757

88

Per

cent

of

patie

nts

with

H

CV

RN

A u

ndet

ecta

ble

Per

cent

of

patie

nts

with

H

CV

RN

A u

ndet

ecta

ble

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

n/N =n/N =

0

10

20

30

40

50

60

70

80

90

100

Patients eligible to receive 24 weeks of total treatment

T12PRT12PR T8PRT8PR PRPR

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

ADVANCE: SVR Rates by eRVR Status

189/212189/212 171/207171/207 28/2928/29 130/332130/33279/15779/15782/15182/151

89898383

9797

54545050

3939

eRVR+eRVR+ eRVR- eRVR-

n/N =n/N =

Per

cent

of

patie

nts

with

SV

RP

erce

nt o

f pa

tient

s w

ith S

VR

0

10

20

30

40

50

60

70

80

90

100

48-week regimen 24-week regimen

T12PRT12PR T8PRT8PR PRPR

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

Overall On-treatment Virologic Failure is Lower in Patients Receiving 12 Weeks of Telaprevir

Criteria for virologic failure:•Met stopping rule•HCV RNA > 1000 IU/ml at week 12 even with HCV RNA decline > 2 log (TVR arms only) •HCV RNA detectable at end of treatment

Criteria for virologic failure:•Met stopping rule•HCV RNA > 1000 IU/ml at week 12 even with HCV RNA decline > 2 log (TVR arms only) •HCV RNA detectable at end of treatment

T12PRVirologic failure 8%

0

4

8

12

16

20

4 12 24 28 36 40 48

Weeks on Treatment

Per

cent

of

Pat

ient

s

0

4

8

12

16

20

4 12 24 28 36 40 48

Weeks on Treatment

T8PRVirologic failure 13%

3%5%

3%

10%

Jacobson IM et al, N Engl J Med 2011;364:2405-16; Kieffer T et al AASLD 2010 Jacobson IM et al, N Engl J Med 2011;364:2405-16; Kieffer T et al AASLD 2010

ADVANCE: SVR by Subgroups

74 7583

7075

62

78 71

7874

Male Female <45 >45-65Age

White Black 1b 1aGenotype

<800K >800KHCV RNA

ADVANCE: Most Common Adverse Events

% of Patients withT12PR

N=363

T8PR

N=364

PR (control)

N=361

Any Adverse Event* 99 99 98

Fatigue 57 58 57

Pruritus 50 45 36

Headache 41 43 39

Nausea 43 40 31

Rash 37 35 24

Anemia 37 39 19

Insomnia 32 32 31

Diarrhea 28 32 22

Influenza-like illness 28 29 28

Pyrexia 26 30 24

Shaded areas: 10% or greater incidence in either TVR groups vs control

ADVANCE: Discontinuation for Adverse Events

D/C T12PR T8PR PR

TVR/Placeboonly

11% 7% 1%

All therapy(overall study)

10% 10% 7%

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

Rash Events During Telaprevir/Placebo Phase

Rash was primarily eczematous and resolved upon cessation of therapy Severe/worsening moderate rash was managed by sequentially discontinuing telaprevir, followed by ribavirin and, if

indicated, peginterferon for continued progression Anorectal symptoms in ~29% with telaprevir

% of Patients with

T12PR

N=363

T8PR

N=364

PR

(control)

N=361

Rash events 56 53 37

Severe rash events 6 4 1

Discontinuation of telaprevir/placebo only due to rash events

7 5 1

Discontinuation of all study drugs due to rash events

1.4 0.5 0

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

Nadir Hemoglobin, Discontinuation for Anemia, and Median Hemoglobin Levels

0

Med

ian

Hem

oglo

bin

(g/d

L)

Weeks

0

11

12

13

14

15

4 8 12 16 20 24

TVR ….

TVR

T12PR (n=363)

T8PR ( (n=364)

PR (control) (n=361)

% of Patients withT12PR

N=363

T8PR

N=364

PR

N=361

Hemoglobin <10 g/dL 36 40 14

Hemoglobin <8.5 g/dL 9 9 2

• Per protocol, anemia was to be managed with RBV dose modifications and ESAs were not allowed

• 1%, 3% and 1% of patients in T12PR, T8PR and PR, respectively discontinued all drugs due to anemia events

• 4%, 2% and 0% of patients in T12PR, T8PR and PR, respectively discontinued telaprevir/placebo only

Hemoglobin nadir during TVR/Pbo Phase Median Hemoglobin

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

IL28B Allele Distribution in ADVANCE was Consistent With Previous Reports for

Treatment-Naïve Patients

Samples from 42% (454/1088) of ADVANCE patients were available in the IL28B dataset

CT49%

CC33%

TT18%

Jacobson IM et al, EASL 2011; DDW 2011

SVR Rates in ADVANCE Patients Genotyped for IL28B

T12PRT8PRPR

45/50 38/45 35/55 48/68 43/76 20/80 16/22 19/32 6/26

Pat

ient

s w

ith S

VR

(%

)P

atie

nts

with

SV

R (

%)

n/N=n/N=

90

71 7384

57 5964

25 23

0

20

40

60

80

100

CC CT TT

Jacobson IM, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB1369.

RVR and eRVR in ADVANCE Patients Genotyped for IL28B

RVR (%) eRVR (%)84

71

16

60 62

2

59

50

0

78

64

16

5751

2

4550

050 45 55 68 76 80 22 32 26 50 45 55 68 76 80 22 32 26

eRVR patients received24 weeks of treatmentJacobson IM, et al. Poster presented at: EASL 2011 Poster LB1369.

CC CT TT

ILLUMINATE Study: 24 vs 48 WeeksAfter eRVR With Telaprevir

Phase 3 Treatment-naïve

Genotype 1

Week 0 12 20 24 48 72

T12/PR

eRVR (extended rapid virologic response): HCV RNA <25 IU/mL at weeks 4 and week 20.

Sherman KE, et al. N Eng J Med 2011;365:1014-24

Telaprevir(750 mg q8h)

PegIFN + RBV

PegIFN + RBV

SVRFollow-Up

PegIFN + RBV

PegIFN + RBV

SVRFollow-Up

With eRVR

SVRFollow-Up

SVRFollow-Up

PegIFN + RBVWithout

eRVR

SVR Rates: ILLUMINATE

0

20

40

60

80

100

ITTITT eRVR+T12PR24eRVR+

T12PR24eRVR+

T12PR48eRVR+

T12PR48eRVR-

T12PR48eRVR-

T12PR48Other(D/C

pre-wk 20)

Other(D/C

pre-wk 20)

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

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

92928888

72726464

2323

388/540388/540 149/162149/162 140/160140/160n/N=n/N= 76/11876/118 23/10023/100

Pat

ient

s W

ith S

VR

(%

)

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

ILLUMINATE: Relapse Rates

9/1599/159 4/1544/154n/N=n/N= 37/46937/469

T12PR24T12PR24 T12PR48T12PR48ITTITT

Pa

tient

s w

ith R

ela

pse

(%

)

8866

33

0

5

10

15

20

Effect of Shortening Therapy in Cirrhotics with eRVR: ILLUMINATE

67

92

12/18 11/12

,Telaprevir package insert,2011

Adverse Events Leading to Study Drug Discontinuations

Total

N=540

Discontinuation of All Study Drugs during Telaprevir Treatment Phase, %

Any Adverse Event 7

Rash events 1

Anemia events 1

Discontinuation of Telaprevir during Telaprevir Treatment Phase, %

Any Adverse Event 12

Rash events 7

Anemia events 2

Overall treatment phase•17% of patients in ITT discontinued all study drugs due to AEsOverall treatment phase•17% of patients in ITT discontinued all study drugs due to AEs

ADVANCE and ILLUMINATE Studies: SVR Rates by Anemia and Ribavirin Dosing Status

Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477.

Pat

ien

ts W

ith

SV

R (

%)

Anemia(n=196/165/361/92)

Anemia Status

76%72%

No Anemia(n=269/259/324/262)

74%

50%

77%73%

41%

T12/PR24T12/PR48

T12/PR PR

70%

Pat

ien

ts W

ith

SV

R (

%)

Dose Reduction(n=172/148/320/89)

Ribavirin Dose Reduction Status

78%73%

No Dose Reduction(n=293/272/565/285)

76%

54%

75% 72%

41%

T12/PR24T12/PR48

T12/PR PR

69%

Retrospective pooled analysis.

Effect of Fibrosis in Pooled ADVANCE and ILLUMINATE Studies

Marcellin P, et al. AASLD 2011, San Francisco, #2105

Liver fibrosis stage

TreatmenteRVR, n (%)

EOT, n (%)

SVR, n (%)

Relapse, n/N (%)

VF, n (%)

F0–F2 T12PR (n=681)444 (65) 563 (83) 539 (79) 16/563 (3) 40 (6)

PR (n=288)25 (9) 183 (64) 140 (49) 42/183 (23) 78 (27)

F3–F4 T12PR (n=222)121 (55) 158 (71) 144 (65) 11/158 (7) 28 (13)

PR (n=73)4 (5) 37 (51) 26 (36) 11/37 (30) 27 (37)

Telaprevir Safety Data:Cirrhosis vs No Cirrhosis

CirrhosisN=82

No cirrhosisN=821

CirrhosisN=21

No cirrhosisN=340

Anemia

Grade 3 55 (67%) 377 (46%) 5 (24%) 85 (25%)

Grade 4 2 (2%) 11 (1%) 0 (0%) 0 (0%)

Neutropenia

Grade 3 8 (10%) 72 (9%) 4 (19%) 39 (11%)

Grade 4 2 (2%) 11 (1%) 0 (0%) 10 (3%)

Thrombopenia

Grade 3 10 (12%) 12 (2%) 0 (0%) 1 (<1%)

Grade 4 1 (1%) 0 (0%) 1 (5%) 0 (0%)

T12 PR(ADVANCE, ILLUMINATE) PR (ADVANCE)

Treatment Naive

Kaufman R et al, HepDart December 2011

Stopping Rules for TelaprevirTreatment Naïve & Experienced

Week 4

HCV RNA >1000 IU/ml

Week 12

HCV RNA>1000 IU/ml

Week 24

HCV RNAdetectable

Stop all therapy

Stop all therapy

Stop all therapy

Telaprevir Package Insert, 2011

Response-Guided Therapy:Telaprevir

Naives (and relapsers)– eRVR+

24 weeks (TPR12/PR12)

– eRVR- 48 weeks (TPR12/PR36)

“Treatment-naïve patients with cirrhosis and eRVR may benefit from additional 36 weeks of PR” (package insert)

Contraindicated Drugs With Telaprevir & Boceprevir

Rifampin Alfuzosin Ergot derivatives Cisapride St. John’s wort Lovastatin, simvastatin, atorvastatin Sildefnafil or tadalafil for PA hypertension Oral midazolam, triazolam

Many other drugs with established or potential drug-drug

interactions that require caution

Telaprevir Package insert

• Interaction with CYP3A4• May occur via inhibition OR induction

Evaluation of Treatment-Emergent Resistant Variants in TVR Phase III trials

74% of treatment-failure pts had RV

255 pts with RVs were followed from Phase III trials

– ADVANCE/ILLUMINATE: 151

– REALIZE: 104 Median follow-up: 11 months Population sequencing 60% lost RVs during follow-up RVs were different in G1a and

G1b, and cleared more rapidly in G1b

Sullivan J, et al. EASL 2011, Berlin, O8

•Long-term analysis of RV after PI failure provides encouragement that re-treatment with PIs will be possible•Reconstitution rates of wt virus are more rapid for G1b than G1a.• Re-treatment studies will be needed for definitive assessment

No RVsMedian time after

EOT, months

V36A/M 68% (115/169)

10

T54A/S 84% (27/32)

4

R155I/K/M/T 59%(100/170)

11

A156S/T/V 86%(19/22)

4

V36M+ R155K

52%(65/124)

14

Summary: Telaprevir andTreatment-Naïve HCV Patients

Telaprevir + peginterferon + ribavirin for 12 weeks, then peginterferon + ribavirin for an additional 12 or 36 weeks

Response-guided therapy is non-inferior to 48 weeks of treatment in patients with an eRVR (undetectable at week 4 and 24)

– May be possible in nearly two-thirds of treatment-naïve patients Rash common; seldom results in overall treatment discontinuation Anemia requires monitoring; potential RBV reductions, epo, transfusions Sustained virologic responses

– Significantly improved over standard of care for overall population and those with impaired response: black, cirrhotic patients

– Ribavirin dose reduction for anemia does not appear to impact response

IL28B may “refine the discussion”, but not decisive in most