Agenda Update on Darunavir: Perry Mohammed Update on Etravirine: Rekha Sinha Update on TMC278:...

Agenda

Update on Darunavir: Perry Mohammed

Update on Etravirine: Rekha Sinha

Update on TMC278: Peter Williams

Update on TMC207: Karel De Beule

HCV pipeline: Daniel de Schryver

Questions and hopefully answers….

Darunavir

Once daily dosing

Monotherapy

Co-infection

Formulation changes

Once daily dosing

DRV/r currently licensed in treatment experienced patients

– 600mg/100mg po bid

Positive CHMP approval Q408

New indication: HIV naïve adult population

– 800mg/100mg po od

Paediatric indication: Q309

– 75mg and 150mg tablets

Once daily: treatment experienced patients?

Tibotec. Data on file.

Target concentration for HIV with FC ≤ 40*

Target concentration for HIV with FC ≤ 10**Pla

sma

con

cen

trat

ion

o

f d

aru

nav

ir/r

(n

g/m

L)

Time (hours)

0

2000

4000

6000

8000

0 2 4 6 8 10 12 14 16 18 20 22 24

Darunavir/r 800/100 mg q.d.: trough levels remain above target concentrations

*resistant virus**wild-type virus

The ODIN study

Worldwide

Pre-treated patients on stable HAART; VL > 1,000

copies/mL no DRV RAMsN = 612

DRV/r QD + OBRn = 306

DRV/r BID + OBRn = 306

Available from www.clinicaltrials.gov accessed November 2008

• Primary endpoint:– non inferiority DRV/r QD vs DRV/r BID

– Results available: Q1 10

Treatment phase (48 weeks)

Monotherapy

European study (13 countries, 250 patients)

First results expected Q309

Follow-up(4 weeks)Screening phase

(4 weeks)

Treatment phase (96 weeks)

Pre-treated patients

on stable HAART

DRV/r 800/100 mg q.d.

DRV/r 800/100 mg q.d. plus 2 NRTIs

Follow-up

Follow-up

Tibotec, data on file.

MONET study

HBV/HCV co-infection

35 (10)

17 (5)

31 (9)

10 (3)

29 (8)

12 (4)

2 (9)

13 (4)

Alanine aminotransferase (ALT)

Grade 2–4

Grade 3–4

Aspartate aminotransferase (AST)

Grade 2–4

Grade 3–4

LPV/r qd or bid

(N=346)

PREZISTA/r qd

(N=343)Laboratory abnormalities, n (%)

ARTEMIS: Liver-related laboratory abnormalities in treatment-naive patients

De Jesus E, et al. Oral Presentation at 47th ICAAC 2007.

Co-infection and treatment-emergent liver-related AEs in treatment-naïve patients in ARTEMIS

†Occurring with an incidence 1% in either treatment group, regardless of severity & causality; laboratory abnormalities reported as AEs are included in the overall incidence of liver-related AEs, but not shown in the table

PREZISTA/r LPV/r

Preferred term, n (%)†Co-infected

(N=43)

Non-co-infected(N=300)

Co-infected(N=48)

Non-co-infected(N=298)

Any liver-related AE 7 (16) 9 (3) 18 (38) 13 (4)

Ascites 1 (2) 0 0 0

Hepatitis 0 1 (<1) 1 (2) 0

Hepatitis C 0 0 3 (6) 2 (<1)

Ortiz R, et al. HEP DART 2007. Abstract 94

13% (n=91) of patients in ARTEMIS were co-infected with HBV and/or HCV at baseline*

New formulations

For treatment-experienced patients: administer from 2 x 300mg DRV tablets bid to 1 x 600mg DRV tablet bid

1. 100mg RTV capsule

2. 300mg DRV tablet (on the market)

1. 100 mg RTV capsule

2. 600mg DRV tablet

100mg RTV 300mg DRV 600mg DRV100mg RTV

DRV/r dosing regimen for treatment-experienced patients

1. 100mg RTV capsule

2. 400mg DRV tablet

DRV/r dosing regimen for treatment-naïve patients under development

100mg RTV 400mg DRV

QD PK Study Design

24-hour PK analysis of etravirine

24-hour PK analysis of darunavir, ritonavir

Fasting lipid assessment

Phase IIa, open label, single arm study (23 subjects enrolled)

Key eligibility criteria

– ARV-naïve adults with HIV-1

– No evidence of resistance to study drugsa

– HBV/HCV co-infection not allowed

aBased on screening or historical resistance assays; presence of <3 ETR resistance-associated mutations (list of 13 RAMs) defined susceptibility to ETR

14 days 14 days 14 days 42 weeks

ETR 400mg qd + TDF/FTC 300/200mg

qd + DRV/r 800/100mg qd

Treatment A Treatment B Treatment C Optional Extension Phase

DRV/r 800/100mg qd + TDF/FTC 300/200mg

qd

ETR 400mg qd + TDF/FTC 300/200mg

qd

DRV/r 800/100mg qd + TDF/FTC 300/200mg qd

Plasma Concentration-time Profile of ETR 400 mg qd

Time (hours)

0 4 8 12 16 20 24

Mea

n ±

SD

pla

sma

ET

R c

once

ntr

atio

n

(ng

/mL

)

0

200

400

600

800

1000

1200 Treatment A: ETR 400mg qd + TDF/FTC 300/200mg qd (n=21)

Protein binding-adjusted EC50 for

WT virus (4 ng/mL)

Treatment B: ETR 400mg qd + TDF/FTC 300/200mg qd + DRV/r 800/100mg qd (n=20)

Changes in Metabolic Parameters from Baseline

Treatment A: ETR + TDF/FTC (Day 14)

Treatment B: ETR + DRV/r + TDF/FTC (Day 28)

Treatment C: DRV/r + TDF/FTC (Day 42)

Baseline, median (range)

Triglycerides Total cholesterol Direct LDL cholesterol HDL cholesterol-2

-1

0

2

1

-2

-1

0

1

-1

-0.5

0

1

0.5

Med

ian

(ra

ng

e [I

QR

]) c

on

cen

trat

ion

, ch

ang

e fr

om

bas

elin

e, m

mo

l/L

-2

-1

0

2

1

2

0.01

0.270.37

-0.080.03

0.28

-0.21-0.16

0.04

0 -0.05 -0.03

0.79 (0.40-2.81) 3.75 (2.84-5.74) 2.38 (1.53-3.59) 1.06 (0.78-1.55)

Changes in Metabolic Parameters from Baseline

InsulinGlucose-2

-1

0

3

1

Med

ian

(ra

ng

e [I

QR

]) c

on

cen

trat

ion

,

chan

ge

fro

m b

asel

ine,

μU

/mL

-18

-9

0

36

9

18

272

Treatment A: ETR + TDF/FTC (Day 14)

Treatment B: ETR + DRV/r + TDF/FTC (Day 28)

Treatment C: DRV/r + TDF/FTC (Day 42)

5.05 (4.16-5.94) 5.00 (1.9-23.0)Baseline, median (range)

Med

ian

(ra

ng

e [I

QR

]) c

on

cen

trat

ion

, ch

ang

e fr

om

bas

elin

e, m

mo

l/L

-0.11 -0.11 -0.08-0.8 0 0

Improving safety and convenience:efavirenz to etravirine switch study

Four UK- based hospitals (40 patients)

First results available Q409

ETR 400 mg q.d.+ BR + placebo

EFV 600 mg q.d.+ BR + placebo

ETR 400 mg q.d.+ BR

12 weeks

12 weeks

Patients on EFV HAART with

CNS or neuropsychiatric

toxicity