TMC278 rilpivirine, an investigational nextgeneration NNRTI, demonstrates longterm efficacy and tole

1
TMC278 (rilpivirine), an investigational
next-generation NNRTI, demonstrates long-term
efficacy and tolerability in ARV-naïve patients
96-week results of study C204

• M Santoscoy,1 P Cahn,2 C Gonsalez,3 W Hao,4 A
  Pozniak,5 P Shalit,6 S Vanveggel,7 K Boven8
• 1Hospital Carlos Mac Gregor IMSS, Mexico City,
  Mexico 2Hospital Juan A Fernández and Fundación
  Huesped, Buenos Aires, Argentina 3Hospital das
  Clíncias, Pinheiros, Brazil 4Beijing Youan
  Hospital, Beijing, China 5Chelsea and
  Westminster NHS Foundation Trust and PKR/SSR,
  London, UK 6Swedish Medical Center, Seattle, WA,
  USA 7Tibotec BVBA, Mechelen, Belgium 8Tibotec
  Inc., Yardley, PA, USA.

2
TMC278 a next-generation NNRTI with potent
anti-HIV-1 activity

• TMC278 has demonstrated potent in-vitro
  anti-HIV-1 activity against wild-type and
  NNRTI-resistant isolates1
• Half-life of 45 hours
• 48-week results from the global Phase IIb
  TMC278-C204 study showed potent and sustained
  efficacy at all doses (25, 75 and 150mg qd) in
  ARV-naïve patients, and was generally well
  tolerated2,3
• Currently in Phase III trials

1de Bethune M-P, et al. CROI 2005. Abstract
5562Pozniak A, et al. CROI 2007. Abstract
144LB 3Yeni P, et al. EACS 2007. Abstract P7.2/08
ARV antiretroviral
3
TMC278-C204 study design
96 weeks

• Ongoing (extended to 5 years), randomized,
  active-controlled, dose-ranging Phase IIb study
  in ARV-naïve patients
• Primary objective to evaluate the TMC278 efficacy
  (ITT-TLOVR) and safety dose-response relationship
  at Week 48

Primary analysis at 48W
Analysis at 96W
Screening and randomization1111 ARV-naïve
patients (N368) HIV RNA ?5,000 copies/mL
EFV 600mg qd 2 NRTIs N89
TMC278 25mg qd 2 NRTIs N93
TMC278 75mg qd 2 NRTIs N95
TMC278 150mg qd 2 NRTIs N91
EFV efavirenz ITT intent to treat TLOVR
time to loss of virologic response NRTI
backbone chosen by investigator and is either
AZT/3TC or TDF/FTC administered as fixed-dose
combinations where available
4
Demographic and baseline characteristics
Median values n88 for EFV 600mg
5
TMC278 high response rate and sustained
virologic response over 96 weeks similar to EFV
HIV-1 RNA lt50 copies/mL to Week 96 (ITT-TLOVR
algorithm)
TMC278 25mg qd (n93) TMC278 75mg qd
(n95) TMC278 150mg qd (n91) EFV 600mg qd (n89)
100 80 60 40 20 0
76
72
71
71
Virologic responders (, 95 CI)
0 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96
Time (weeks)
CI confidence interval
6
TMC278 potent antiviral efficacy at Week 48
sustained to Week 96
AE adverse eventPatients with loss of
virologic response, patients who never achieved
confirmed viral load lt50 copies/mL or patients
who discontinued before reaching Week 96 due to
lack of virologic efficacy
7
TMC278 continued CD4 increases through Week 96
Hatched bars Week 48
Solid bars Week 96
122
145
143
127
146
172
159
160
200
150
Mean change in CD4 cell countfrom baseline
(cells/mm3, 95 CI)
100
50
0
TMC278 25mg qd (n93)
TMC278 75mg qd (n95)
TMC278 150mg qd (n91)
EFV 600mg qd (n88)
For premature discontinuations, subsequent
timepoints were imputed with baseline value up to
week 96 (non-completer status equals failure
imputation algorithm) Intermediate missing values
were imputed using last observation carried
forward
8
A limited number of patients experienced
virologic failure and developed RAMs on
TMC278-based therapy

• Very few patients experienced virologic failure
  with RAMs
• 6 (17/279) in the TMC278 arms
• 7 (6/89) in the EFV arm
• The proportion of patients in whom
  treatment-emergent NNRTI RAMs developed was
  similar across arms
• 56 (5/8) in the TMC278 25mg qd group
• 60 (3/5) in the TMC278 75mg qd group
• 33 (1/3) in the TMC278 150mg qd group
• 60 (3/5) in the EFV arm
• Resistance findings to be explored further in
  Phase III trials

Sequence information not available in 2 VF
failures (1 in TMC278 75mg arm and 1 in EFV arm)
9
All TMC278 doses were safe and well tolerated,
with no consistent association between safety
assessments and TMC278 dose
Summary of treatment-emergent AEs, regardless of
severity and causality
Investigations included laboratory assessments
and electrocardiograms
10
Incidences of rash, nervous system- and
psychiatric-related AEs were lower with TMC278
than with EFV
Summary of NNRTI AEs of interest, regardless of
severity and causality
Well-described AEs associated with current
NNRTIs and occurring in 5 of TMC278- or
EFV-treated patients All rashes were grade 1 or
2, except for one patient with grade 3 rash in
the TMC278 75mg group (associated with fever)
probably related to dapsoneplt0.01 vs EFV
plt0.05 vs EFV (Fishers exact test)
11
Increases in lipid parameters were lower with
TMC278 than with EFV

• No TMC278 dose relationship for mean changes in
  lipid parameters

Mean change from baseline (SD) at 96 weeks
TC total cholesterol LDL-C low-density
lipoprotein-cholesterol HDL-C high-density
lipoprotein-cholesterol TG triglyceridesplt0.0
1, p0.19 for EFV vs TMC278 (nonparametric
Wilcoxon rank sum test, post-hoc analysis)
12
Additional investigations

• Endocrine
• No clinically relevant changes in adrenal and
  thyroid parameters were observed
• ECG
• Increases in QTc interval were seen with all
  TMC278 doses and EFV up to 48 weeks, which then
  stabilizedup to Week 96
• increases were primarily seen with the AZT/3TC
  backbone
• mean increase was lowest with TMC278 25mg

13
Conclusions

• Once-daily oral TMC278 at all doses demonstrated
  a high response rate and sustained virologic
  response over 96 weeks
• TMC278 was generally safe and well tolerated
• Incidences of rash, nervous system- and
  psychiatric-related AEs and increase in lipids
  were significantly lower with TMC278 than with
  EFV
• There were trends suggesting a favourable profile
  of TMC278 25mg compared with the higher dose
  groups
• Both efficacy and safety of TMC278 were well
  maintained between 48 and 96 weeks
• TMC278 is being further evaluated in Phase III
  trials at a dose of 25mg qd

14
Acknowledgements

• The authors would like to thank the patients who
  participated in the study, the study centre
  staff, DSMB members, Tibotec study personnel and
  the following principal investigators