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48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ARV-naïve patients. A Pozniak , J Morales-Ramirez, L Mohapi, M Santoscoy, P Chetchotisakd, M Hereygers, S Vanveggel, M Peeters, B Woodfall and K Boven.

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48-week primary analysis of trial TMC278-C204:TMC278 demonstrates potent and sustained efficacy in ARV-naïve patients

A Pozniak, J Morales-Ramirez, L Mohapi,

M Santoscoy, P Chetchotisakd, M Hereygers,

S Vanveggel, M Peeters, B Woodfall and K Boven

14th Conference on Retroviruses and Opportunistic Infections

Los Angeles, USA, 25–28 February 2007

Abstract: J-1010, Paper: 144LB


Tmc278 l.jpg
TMC278

  • TMC278, a next generation NNRTI, has demonstrated in vitro and in vivo activity against wild-type and NNRTI resistant isolates1

  • TMC278 has a terminal half-life of 45 hours in humans

  • All doses (25–150mg) of TMC278 significantly reduced viral load in a Phase IIa study in ARV-naïve patients2

1de Bethune M-P, et al. CROI 2005. Abstract 5562Goebel F, et al. CROI 2005. Abstract 160


Tmc278 c204 phase iib arv na ve patients l.jpg
TMC278-C204 Phase IIb, ARV-naïve patients

96 weeks

VL 5,000 copies/mL

Sensitive to NRTIs and no NNRTI RAMs

  • Randomized controlled study

  • TMC278 blinded for all 3 dose groups versus open label efavirenz

  • Stratification factors

    • Investigator-selected NRTI backbone: Combivir® (75.3%) or Truvada® (24.7%) (given as combination or individual components)

    • Region (Asia and Africa; US, Europe and Russia; Latin America)

EFV 600mg qd + 2 NRTIs (n=89)

TMC278 25mg qd + 2 NRTIs (n=93)

Screening

TMC278 75mg qd + 2 NRTIs (n=95)

TMC278 150mg qd + 2 NRTIs (n=91)

VL = viral load; RAM = resistance associated mutation; EFV = efavirenz


Demographic and baseline characteristics l.jpg
Demographic and baseline characteristics

*No differences between TMC278 dose groups

†Median values and (range)


Patient disposition at week 48 primary efficacy endpoint itt population l.jpg
Patient disposition at Week 48Primary efficacy endpoint, ITT population

*TLOVR = time to loss of virologic response; NC=F = non-completer = failure; ITT = intent to treat.

Virologic response and loss of response need confirmation with subsequent VL measurement.

†Not related to TMC278


Vl 50 copies ml through 48 weeks observed l.jpg
VL <50 copies/mL through 48 weeks (observed)

TMC278 25mg qd

TMC278 75mg qd

TMC278 150mg qd

EFV 600mg qd

96%

100

80

60

40

20

0

93%

92%

89%

Virologic responders (%, 95% CI)

0 2 4 8 12 16 20 24 32 40 48 56

Time (weeks)

TMC278 25mg N = 89

TMC278 75mg N = 93

TMC278 150mg N = 89

EFV 600mg N = 83

90 88 81 84 81 81 81 80 78 28

92 90 92 88 88 87 83 81 81 26

87 86 83 81 80 79 77 74 75 23

84 82 83 79 80 80 80 79 76 27


Vl 50 copies ml through 48 weeks tlovr primary efficacy endpoint itt population nc f l.jpg

100

80

60

40

20

0

0

2

4

8

12

16

20

24

32

40

48

VL <50 copies/mL through 48 weeks (TLOVR)Primary efficacy endpoint, ITT population (NC=F)

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

81%

81%

80%

77%

Virologic responders (%, 95% CI)

Time (Weeks)

CI = confidence interval


Change in log 10 plasma vl through 48 weeks l.jpg

0

2

4

8

12

16

20

24

32

40

48

Change in log10 plasma VL through 48 weeks

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

0.0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

Mean change in log10 VL (95% CI)

Time (weeks)

For premature discontinuations: data imputed with baseline value (NC=F)For missing values: last observation carried forward (LOCF)


Change in cd4 cell count through 48 weeks l.jpg

0

2

4

8

12

16

20

24

32

40

48

Change in CD4 cell count through 48 weeks

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

180

160

145

140

143

127

120

125

Mean change (95% CI) from baseline in CD4 cell counts (x 106/L)

100

80

60

40

20

0

Time (weeks)

For premature discontinuations: data imputed with baseline value (NC=F)For missing values: last observation carried forward (LOCF)


Most common aes at least possibly related to tmc278 or efavirenz l.jpg
Most common AEs* at least possibly related to TMC278 or efavirenz

*Occurring in >5% of patients in all TMC278 groups combined or control


Nnrti class effects any grade irrespective of causality l.jpg
NNRTI class effects, any grade, irrespective of causality efavirenz

*All rashes were grade 1/2 except one patient with grade 3 rash plus fever (75mg TMC278 group) probably related to dapsone


Serious adverse events saes and grade 3 4 adverse events aes l.jpg
Serious adverse events (SAEs) and grade 3/4 adverse events (AEs)

  • SAEs at least possibly related to treatment

    • TMC278 25mg: 3 patients; 75mg: 0 patients; 150mg: 2 patients and EFV: 1 patient

  • One death in TMC278 75mg qd group (not related) due to pneumonia, septic shock

  • Difference in G3 and G4 AEs largely due to investigations reported as AE (11.1% in TMC278 and 6.7% in EFV) but no difference in G3 and G4 lab abnormalities


Treatment emergent grade 3 4 laboratory abnormalities l.jpg
Treatment-emergent grade 3/4 laboratory abnormalities adverse events (AEs)

All grade 3/4 lab abnormalities: TMC278 22%, efavirenz 20%

*Relative to the number of patients with available data for that parameter


Laboratory data over time l.jpg
Laboratory data over time adverse events (AEs)

Lipids

  • No TMC278 dose relationship for mean changes in lipid parameters

    Endocrine tests

  • No clinically relevant changes in endocrine laboratory parameters

LDL = low density lipoprotein; HDL = high density lipoprotein


Tmc278 c204 conclusions l.jpg
TMC278-C204: adverse events (AEs)conclusions

  • TMC278 demonstrated potent and sustained antiviral efficacy over 48 weeks: 77–81% (TLOVR, NC= F, <50 copies/mL)

  • TMC278 was generally safe and well-tolerated

  • Incidence of rash and nervous system-related events and total cholesterol/triglycerides were lower with TMC278 than with EFV

  • The 75mg dose, one pill once daily, has been selected for further development in treatment-naïve HIV patients


Tmc278 c204 acknowledgements l.jpg
TMC278-C204: acknowledgements adverse events (AEs)

The authors would like to thank the patients that participated in the study, the study center staff, DSMB members, Tibotec study personnel and the principal investigators:


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