Teleprevir User Information

8/13/2019 Teleprevir User Information

1/20

Telaprevir named patient

ALASTAIR MILLER MA FRCP DTM&H

Consultant Physician

Tropical & Infectious Disease Unit (3Z)

Royal Liverpool University Hospital

Honorary FellowLiverpool School of Tropical Medicine


2/20

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding

and endocytosis

Fusion and

uncoating

Transport

and release

(+) RNA

Translation and

polyprotein

processingRNA replication

Virion

assembly

Membranous

web

ER lumen

LD

LD

ER lumen

LD

NS3/4 protease

inhibitors NS5B polymerase inhibitors

Nucleoside/nucleotide

Nonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors


3/20

33

Telaprevir

Developed for G1 treatment nave and all prior treatment failures

Telaprevir is an add-on therapy to SOC (PegIFN-RBV) for G1 treatment

Dosing in Phase 3 trials is 750 mg every 8 hours orally with food

TVR Treatment duration is 12 weeks for all patients

Telaprevir is not currently licensed in the UK


4/20

ADVANCE: study design (N=1088)

240 48 72

Weeks

128 36

Follow-upPR48

(control)

(N=361)

SVRPbo + PR PR

Follow-upSVR

TVR+

PR

T8PR

(N=364)

PR

Pbo +PR

Follow-up

SVReRVR+

PR

Follow-up

eRVR

T12PR

(N=363) TVR + PR

Follow-upSVR

PR

eRVR+

Follow-up

SVR

PR

Follow-up

eRVR

Peg-IFN alfa-2a dose: 180 g/week; RBV dose: 1000 or 1200 mg/day

eRVR: extended rapid virologic response (undetectable HCV RNA at Weeks 4 and 12)

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


5/20

ADVANCE: SVR rates in Telaprevir-treated Patients

Compared with PR Alone

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


6/20

ILLUMINATE : study design (N=540)

0 12 20 20 24 36 48 60 72

T12PR PR

Follow-up

SVR

Follow-up

SVR

PR

PR

Randomized TreatmentseRVR+Non-inferiority (NI)

Follow-up

72 weeks

eRVR+

T12PR24

N=162

eRVR+

T12PR48N=160

Follow-up

SVR

PR

Assigned Treatment

eRVR eRVR

T12PR48

N=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


7/20

ILLUMINATE: SVR Rates Across Treatment Groups

SVR

(%)

ITT

388/540

eRVR+

T12PR48

140/160n/N=

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

eRVR+

T12PR24

149/162

eRVR

T12PR48

76/118

Other*

23/100

4.5%(2-sided 95% CI = 2% to +11%)

*Patients who prematurely discontinued ILLUMINATE for any reason before Week 20randomization were categorized as Other (N=100)

65% patients eligible for 24wk total treatment


8/20

Summary: Nave Patients

Peg-IFN +

RBVTelaprevir +

Peg-IFN + RBV

Peg-IFN + RBV

W4-12

eRVR

YES

NO

0 4 8 12 24 28 48

Weeks

Short duration (24W): 58-65%

Overall SVR: 72-75%

SVR: 89-92%

SVR: 54-64%

Apply stopping rules for weeks 4, 12, 24

Schematic for illustration purposes only


9/20

Definitions of prior Peg-IFN/RBV therapy failure

Detection limit

Relapse

Treatment

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

HCVRNA

level

Weeks

2 log10 drop

Null response

Partial response

Non-response

Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:4652

Neumann A, et al. Science 1998;282:1037; De Bruijne J, et al. Neth J Med 2008;66:31122


10/20

REALIZE: study design (N=662)

484 160 128

Weeks

72

T12/PR48Peg-IFN + RBV

TVR +

Peg-IFN + RBV

Pbo +

Peg-IFN +

RBVN=266Follow-up

SVR assessment

TVR +Peg-IFN + RBV

Peg-IFN + RBV

LI T12/

PR48

N=264

Follow-upPbo +

Peg-IFN +

RBV

PR48

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

N=132

Follow-up

Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14

LI: lead-in; Pbo: placebo; TVR: telaprevir

Randomization was stratified by viral load and prior response category

Stopping rules applied for telaprevir (Weeks 4, 6, and 8) and Peg-IFN/RBV (Weeks 12, 24 , and 36)

Peg-IFN alfa-2a = 180g/week subcutaneously; RBV = 10001200mg/day

TVR = 750mg every 8 hours


11/20

REALIZE: SVR in prior relapsers, partial responders and null responders

PR48

4/27

T12/

PR48

29/49

SVR(%

)

Prior relapsers Prior partial

responders

LI T12/

PR48

26/48

n/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


12/20

Summary of Rash Data from Phase 2 and 3

Trials: Telaprevir Treatment Phase

Data on file: TVR/DoF/January2011/EMEA01

>90% of all rash =

mild/moderate

Incidenceofrash(%)

Features:

Typically pruritic and eczematous, and involving


13/20

Grading of Skin Eruption Severity Grade 1 (Mild): localized skin eruption and/or a skin eruption with limited distribution, with or

without associated pruritus

Grade 2 (Moderate): diffuse skin eruption involving up to 50% of body surface area, with or

without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration

Grade 3 (Severe): generalized skin eruption involving either >50% of body surface area

OR rash presenting with any of the following characteristics

Rash with vesicles or bullae, superficial ulceration of mucous membranes, epidermal detachment, atypical or typical target

lesions, palpable purpura/non-blanching erythema, drug reaction with eosinophilia and systemic symptoms (DRESS),erythema multiforme (EM), acute generalized exanthematous pustulosis (AGEP), or severe alteration of general state

A skin eruption with appearance of new significant systemic signs and symptoms related to onset and/or progression of

skin eruption must be considered as grade 3

Grade 4 (life-threatening):

Toxic epidermal necrolysis, Stevens-Johnson syndrome, skin eruption with generalized

bullous eruption

Telaprevir French cohort ATU Protocol

Available at http://www.afssaps.fr


14/20


15/20

Current status

FDA approved

EMA licence either September or June

Depends on fast track

Drug free until licensed


16/20

Eligibility

Age 18-70

Chronic HCV GT1

Detectable HCV RNA (no level specified) Documented liver fibrosis

Biopsy or fibroscan

>= F3 (Ishak or Metavir)

Usual pregnancy rules

TVR affects OCP


17/20

Exclusion

Eligible for clinical trial of teleprevir

Infected with non GT1 HCV

Previously received DAA (PI or polymeraseinhibitors)

HCC or decompensated liver disease

AFP and US within 4 months

Coinfection with HBV or HIV


18/20

Exclusions

Lab abnormalities

ANC


19/20

Exclusions

Uncontrolled thyroid abnormalities

Anaemia risk

QT problems

Uncontrolled/severe Thyroid disease

Mental health issues

Seizure disorder Immune mediated disease

Eye problems


20/20

Process

Not a trial therefore no requirement for ethics

or informed consent

Drugs ordered directly from pharmacy

Will need to liaise with pharmacy

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