TMC278 Update,
30th January 2009
 C204 data
 ECHO and THRIVE - Phase III studies
 New TMC278 formulations
Peter Williams
Tibotec BVBA, Mechelen, Belgium
TMC278-C204: study design
96 weeks
Primary analysis at Week 48
Screening and
randomisation
1:1:1:1
ARV-naïve
patients
(N=368)
Viral load
5,000
copies/mL



Analysis at Week 96
EFV 600mg qd + 2 NRTIs
N=89
TMC278 25mg qd + 2 NRTIs
N=93
TMC278 75mg qd + 2 NRTIs
N=95
TMC278 150mg qd + 2 NRTIs N=91
Ongoing (extended to 5 years), randomised, active-controlled, dose-ranging Phase IIb study
in ARV-naïve patients
TMC278 blinded for all three groups until Week 96 versus open-label EFV
Primary objective to evaluate the TMC278 efficacy (ITT-TLOVR) and safety dose-response
relationship at Week 48
EFV = efavirenz; ITT = intent to treat; TLOVR = time to loss of virological response; NRTI backbone chosen by
investigator and is either AZT/3TC or TDF/FTC administered as fixed-dose combinations where available
TMC278: high and sustained virological response rate
over 96 weeks
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
A limited number of patients experienced virological
failure and developed RAMs on TMC278-based therapy
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Most common grade 2–4 AEs* at least possibly related
to TMC278 or EFV
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Incidences of neurological- and psychiatric-related AEs
were lower with TMC278 than with EFV
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Incidence of rash was lower with TMC278 than with EFV
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Increases in lipid parameters were lower with TMC278
than with EFV
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Conclusions
CONFIDENTIAL RESULTS ONLY FOR
UK-CAB MEETING
Confidential Tibotec Presentation
Phase III trial, TMC278-C209 - ARV naïve
patients
96 weeks
 Primary analysis-48 weeks
TMC278 25 mg qd + TDF/FTC N=340
Screening
Efavirenz 600 mg qd + TDF/FTC N=340
• Randomized, double blind, double dummy
• Non-inferiority, primary efficacy endpoint % of subjects with viral
load <50 HIV-1 RNA copies/mL (TLOVR),
• ARV-naïve subjects, primary NNRTI resistance excluded
• Backbone fixed to tenofovir + emtricitabine
• RECRUITMENT START APR 2008
Confidential Tibotec Presentation
Phase III trial, TMC278-C215 - ARV naïve
patients
96 weeks
 Primary analysis-48 weeks
TMC278 25 mg qd + 2 NRTIs N=340
Screening
Efavirenz 600 mg qd + 2 NRTIs N=340
• Randomized, double blind, double dummy
• Non-inferiority, primary efficacy endpoint % of subjects with viral
load <50 HIV-1 RNA copies/mL (TLOVR)
• ARV-naïve subjects, primary NNRTI resistance excluded
• Backbone WAS fixed to abacavir + lamivudine
• Positive test result for HLA-B*5701 excluded
• RECRUITMENT START MAY 2008
Confidential Tibotec Presentation
TMC278 new formulations


TMC278 for children

Oral formulation to allow dosage adjustment by bodyweight in
younger children

Relative bioavailability study of 3 concept formulations
ongoing
TMC278 LA

Once monthly injectable formulation

Maintenance therapy with a companion injectable ARV

Pre-exposure prophylaxis
Confidential Tibotec Presentation
Formulation and clinical methods

Innovative nanosuspension*

100mg TMC278 base per mL

particles of pure TMC278,
average size of 200nm

sterile, stable formulation
with neutral pH

TMC278 LA single doses,
given as intramuscular (IM)
and subcutaneous (SC)
injections

PK and injection-site tolerability were evaluated
*using NanoCrystal® technology (under license from Elan Corporation, Ireland)
LA = long acting
Confidential Tibotec Presentation
Single-dose TMC278 LA provided sustained plasma levels
for up to 12 weeks in humans
120
SC 200mg
SC 400mg
100
SC 600mg
TMC278 (ng/mL)
80
IM 200mg
IM 400mg
60
IM 600mg
40
20
0
0

1
2
3
4
5
6
7
Time (weeks)
8
9
10
11
Dose proportionality and similar PK profiles after single SC and IM injections
Confidential Tibotec Presentation
12
Conclusions on TMC278 LA

Injectable LA formulations may provide a new paradigm in ARV use and
may facilitate long-term compliance

TMC278 LA is a promising depot formulation; the concept is viable
 single 400mg and 600mg doses gave prolonged TMC278 plasma
exposure of approximately 20ng/mL after 8 weeks
 PK exposures were comparable after IM and SC injections
 favorable safety and tolerability: no serious AEs, grade 3 or 4 AEs
or rash



injections were well tolerated, particularly when administered IMg;
indurations were more frequent after SC than after IM injections
placebo injections were better tolerated than injections with TMC278 LA;
600mg IMg injections were better tolerated than 600mg SC and than 400mg
IMd injections
Next steps: to perform a multiple-dose trial in HIV-negative healthy
volunteers; continue with IM and SC (allowing self-administration)
injections
Confidential Tibotec Presentation