Telaprevir named patient

ALASTAIR MILLER MA FRCP DTM&H

Consultant Physician
Tropical & Infectious Disease Unit (3Z)
Royal Liverpool University Hospital
Honorary Fellow
Liverpool School of Tropical Medicine

HCV Life Cycle and DAA Targets

Receptor binding
and endocytosis

Transport
and release

Fusion and
uncoating

ER lumen

(+) RNA

LD

LD

Translation and
NS3/4 protease
polyprotein
inhibitors
processing

Virion
assembly

LD

Membranous
web
ER lumen

NS5BRNA
polymerase
inhibitors
replication
Nucleoside/nucleotide
Nonnucleoside

NS5A* inhibitors
*Role in HCV life cycle not well defined

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

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

33

Telaprevir is not currently licensed in the UK

ADVANCE: study design (N=1088)

PR48
(control)
(N=361)

SVR
Pbo + PR

PR

Follow-up

SVR

eRVR+

Follow-up

T12PR
(N=363)

TVR + PR

PR

Follow-up

eRVR

SVR
PR
eRVR+

SVR
Follow-up

TVR
+
PR

T8PR
(N=364)

Follow-up

Pbo +
PR

PR

Follow-up

eRVR

SVR
Follow-up

PR

12

24

36
Weeks

48

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

72

ADVANCE: SVR rates in Telaprevir-treated Patients

Compared with PR Alone
6% difference
(95% CI: 12.5% to +0.6%)
*
*

n/N =

PR48

T12PR

T8PR

158/361

271/363

250/364

58% patients eligible for 24wk total treatment

*p<0.0001 vs PR48

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

ILLUMINATE : study design (N=540)

SVR
PR

T12PR

Follow-up

eRVR+
T12PR24
N=162

Non-inferiority (NI)

Randomized Treatments

eRVR+

PR

Follow-up

72 weeks

SVR

eRVR+
T12PR48
N=160

SVR

eRVR
T12PR48
N=118

Follow-up

PR

Assigned Treatment
eRVR
Follow-up

PR

12

20

20 24

36

48

60

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

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

72

ILLUMINATE: SVR Rates Across Treatment Groups

SVR (%)

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

n/N=

ITT

eRVR+
T12PR24

eRVR+
T12PR48

eRVR
T12PR48

Other*

388/540

149/162

140/160

76/118

23/100

65% patients eligible for 24wk total treatment

*Patients who prematurely discontinued ILLUMINATE for any reason before Week 20
randomization were categorized as Other (N=100)
Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

Summary: Nave Patients

Short duration (24W): 58-65%

Overall SVR: 72-75%

W4-12
eRVR
YES Peg-IFN +
Telaprevir +
RBV
Peg-IFN + RBV
Peg-IFN + RBV
NO
0

12

Weeks

24

28

SVR: 89-92%
SVR: 54-64%
48

Apply stopping rules for weeks 4, 12, 24

Schematic for illustration purposes only

Definitions of prior Peg-IFN/RBV therapy failure

Null response

HCV RNA level

Non-response

Relapse

2 log10 drop
Partial response

Detection limit

Treatment
0

12

16

20

24

28

32

36 40
Weeks

44 48

52

56

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

60

64

68

72

REALIZE: study design (N=662)

PR48
(control)

Pbo + Peg-IFN + RBV

Peg-IFN + RBV

Follow-up

Peg-IFN + RBV

Follow-up

Peg-IFN + RBV

Follow-up

N=132

LI T12/
PR48

Pbo +
Peg-IFN +
RBV

N=264

T12/PR48

TVR +
Peg-IFN + RBV

Pbo +
Peg-IFN +
RBV

TVR +
Peg-IFN + RBV

N=266

12

16

72

48
Weeks

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

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

SVR assessment

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

Prior relapsers

Prior partial
responders

Prior null
responders

*
*

SVR (%)

PR48

LI T12/
PR48

T12/
PR48

PR48

LI T12/
PR48

T12/
PR48

PR48

LI T12/
PR48

T12/
PR48

124/141

121/145

4/27

26/48

29/49

2/37

25/75

21/72

*p<0.001 vs PR48; post-hoc analysis

16/68
n/N=

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

Incidence of rash (%)

Incidence of rash (%)

Summary of Rash Data from Phase 2 and 3

Trials: Telaprevir Treatment Phase

Features:
Typically pruritic and eczematous, and involving <30% BSA
Progression was infrequent (<10% of cases)
Time to onset:
Approximately 50% of rashes started during the first 4 weeks
But rash can occur at any time during telaprevir treatment

Data on file: TVR/DoF/January2011/EMEA01

>90% of all rash =

mild/moderate

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

Telaprevir Interruption Guidance

Telaprevir must not be restarted if discontinued
Grade 1

Grade 2

Telaprevir interruption generally not necessary

Telaprevir interruption generally not necessary

If interruption is necessary, e.g. for progressive rash, recommend discontinue
telaprevir first
If no rash improvement within 7 days of stopping telaprevir, (or earlier if
worsening rash) consider interrupting ribavirin

Rash
Grade 3
Non SJS/TEN/
EM/DRESS/
AGEP

SCARs
SJS/TEN/
EM/DRESS/
AGEP

Telaprevir must be stopped immediately

If no improvement in rash within 7 days of stopping
telaprevir, (or earlier if rash worsens) interrupt ribavirin

Permanent discontinuation of ALL TREATMENT is required

AGEP: acute generalized exanthematous pustulosis; DRESS: drug rash with eosinophilia and systemic symptoms; EM: erythema multiforme; TEN: toxic epidermal necrolysis; SCAR:
severe cutaneous adverse reaction; SJS: Stevens Johnson syndrome

Data on file:
TVR/DoF/January2011/EMEA01

Current status
FDA approved
EMA licence either September or June
Depends on fast track

Drug free until licensed

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

Exclusion
Eligible for clinical trial of teleprevir
Infected with non GT1 HCV
Previously received DAA (PI or polymerase
inhibitors)
HCC or decompensated liver disease
AFP and US within 4 months

Coinfection with HBV or HIV

Exclusions
Lab abnormalities

ANC <1500
Platelets < 90 000
Hb < 12 F <13 M
Creatinine clearance < 50
K < 3.5
INR >1.5
Albumin <33
Bili > 1.8 X ULN (unless Gilberts)

Exclusions

Uncontrolled thyroid abnormalities

Anaemia risk
QT problems
Uncontrolled/severe

Thyroid disease
Mental health issues
Seizure disorder
Immune mediated disease
Eye problems

Process
Not a trial therefore no requirement for ethics
or informed consent
Drugs ordered directly from pharmacy
Will need to liaise with pharmacy