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
Fusion and uncoating

Transport and release

(+) RNA

ER lumen
LD

LD

Virion assembly

Translation and NS3/4 protease polyprotein inhibitors processing

LD

Membranous web ER lumen

NS5B polymerase inhibitors RNA 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

3 3

Telaprevir is not currently licensed in the UK

ADVANCE: study design (N=1088)

PR48 (control) (N=361) SVR Pbo + PR PR Follow-up

eRVR+

SVR Follow-up Follow-up SVR PR Follow-up SVR Follow-up Follow-up SVR

T12PR (N=363)

TVR + PR

PR

eRVR

eRVR+

T8PR (N=364)

TVR + PR

Pbo + PR

PR

eRVR

PR

Follow-up

12

24

36 Weeks

48

72

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

ADVANCE: SVR rates in Telaprevir-treated Patients Compared with PR Alone

6% difference (95% CI: 12.5% to +0.6%) * *

PR48
n/N =
158/361

T12PR
271/363

T8PR
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 Follow-up Follow-up

72 weeks

eRVR+ T12PR24 N=162

T12PR

PR

eRVR+

Randomized Treatments

Non-inferiority (NI)
SVR

PR

Follow-up

eRVR+ T12PR48 N=160

Assigned Treatment
eRVR

SVR

PR

Follow-up

eRVR T12PR48 N=118

12

20

20 24

36

48

60

72

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

ILLUMINATE: SVR Rates Across Treatment Groups

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

SVR (%)

ITT

eRVR+ T12PR24
149/162

eRVR+ T12PR48
140/160

eRVR T12PR48
76/118

Other*

n/N=

388/540

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

W4-12 eRVR YES Peg-IFN + Telaprevir + RBV Peg-IFN + RBV Peg-IFN + RBV NO 0 4 8 12

Short duration (24W): 58-65% Overall SVR: 72-75% SVR: 89-92% SVR: 54-64%
48

Weeks

24

28

Apply stopping rules for weeks 4, 12, 24

Schematic for illustration purposes only

Definitions of prior Peg-IFN/RBV therapy failure

Null response Relapse Non-response

HCV RNA level

2 log10 drop
Partial response

Detection limit

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

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

REALIZE: study design (N=662)

PR48 (control) N=132

Pbo + Peg-IFN + RBV

Peg-IFN + RBV

Follow-up

LI T12/ PR48 N=264

Pbo + Peg-IFN + RBV

TVR + Peg-IFN + RBV

Peg-IFN + RBV

Follow-up

T12/PR48
N=266

TVR + Peg-IFN + RBV

Pbo + Peg-IFN + RBV

Peg-IFN + RBV

Follow-up

12

16 Weeks

48
SVR assessment

72

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

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

Prior relapsers
* *

Prior partial responders

Prior null responders

SVR (%)

PR48
*p<0.001 vs PR48; post-hoc analysis

LI T12/ PR48

T12/ PR48

PR48

LI T12/ PR48

T12/ PR48

PR48

LI T12/ PR48

T12/ PR48

16/68 n/N=

124/141

121/145

4/27

26/48

29/49

2/37

25/75

21/72

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

Summary of Rash Data from Phase 2 and 3 Trials: Telaprevir Treatment Phase
Incidence of rash (%) Incidence of rash (%)

>90% of all rash = mild/moderate

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

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 Telaprevir interruption generally not necessary

Grade 2

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

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

SCARs SJS/TEN/ EM/DRESS/ AGEP

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