tmc278 update, 30th january 2009 c204 data echo and thrive - phase iii studies new tmc278...

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



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


A limited number of patients experienced virological failure and developed RAMs on TMC278-based therapy



Most common grade 2–4 AEs* at least possibly related to TMC278 or EFV



Incidences of neurological- and psychiatric-related AEs were lower with TMC278 than with EFV



Incidence of rash was lower with TMC278 than with EFV



Increases in lipid parameters were lower with TMC278 than with EFV



Conclusions



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


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


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


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


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


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

tmc278 update, 30th january 2009 c204 data echo and thrive - phase iii studies new tmc278...

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