tmc278 update, 30th january 2009 c204 data echo and thrive - phase iii studies new tmc278...
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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
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
Screening and randomisation
1:1:1:1
ARV-naïve patients (N=368)
Viral load 5,000
copies/mL
Primary analysis at Week 48 Analysis at Week 96
96 weeks
TMC278 25mg qd + 2 NRTIs N=93
TMC278 75mg qd + 2 NRTIs N=95
TMC278 150mg qd + 2 NRTIs N=91
EFV 600mg qd + 2 NRTIs N=89
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
Confidential Tibotec Presentation
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
• 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
Screening
TMC278 25 mg qd + TDF/FTC N=340
Efavirenz 600 mg qd + TDF/FTC N=340
96 weeks Primary analysis-48 weeks
Confidential Tibotec Presentation
Phase III trial, TMC278-C215 - ARV naïve patients
• 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
Screening
TMC278 25 mg qd + 2 NRTIs N=340
Efavirenz 600 mg qd + 2 NRTIs N=340
96 weeks Primary analysis-48 weeks
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
Dose proportionality and similar PK profiles after single SC and IM injections
120
100
80
60
0
1 2 3 4 5 6 7 8 9 1211100
40
20
Time (weeks)
TM
C27
8 (n
g/m
L)
SC 200mg
SC 400mg
SC 600mg
IM 200mg
IM 400mg
IM 600mg
Confidential Tibotec Presentation
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