agenda update on darunavir: perry mohammed update on etravirine: rekha sinha update on tmc278:...
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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….
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Darunavir
Once daily dosing
Monotherapy
Co-infection
Formulation changes
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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
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Once daily: treatment experienced patients?
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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
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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)
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Monotherapy
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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
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HBV/HCV co-infection
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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.
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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*
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New formulations
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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
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1. 100mg RTV capsule
2. 400mg DRV tablet
DRV/r dosing regimen for treatment-naïve patients under development
100mg RTV 400mg DRV
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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
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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)
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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)
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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
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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