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 InfectionsLos Angeles, USA, 25–28 February 2007 Abstract: J-1010, Paper: 144LB

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

Screening

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

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

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

VL 5,000 copies/mL

Sensitive to NRTIs and no NNRTI RAMs

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

96 weeks

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

TMC278-C204 Phase IIb, ARV-naïve patients

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)

Demographic and baseline characteristics

Characteristic

All TMC278*

n=279EFV 600mg

n=89

Gender, % female 33.0 32.6

Race, % Caucasian 44 47

Age, years† 35 (19–67)

35 (21–63)

VL, log10 copies/mL† 4.84 (2.16–7.13)

4.88 (3.37–6.41)

VL, copies/mL† 69,300

(144–13,600,000)

75,100

(2,320–2,570,000)

CD4 cell count, cells/mm3† 200 (5–758)

207 (3–970)

Duration of known HIV infection, years†

1.0 (0–21)

1.0 (0–15)

*No differences between TMC278 dose groups†Median values and (range)

Patient disposition at Week 48Primary efficacy endpoint, ITT population

Parameter, n (%)

TMC278

EFV 600mgn=89

25mg qdn=93

75mg qdn=95

150mg qdn=91

VL <50 copies/mL* 75 (81) 76 (80) 70 (77) 72 (81)

Virologic failure 8 (9) 5 (5) 6 (7) 5 (6)

Death 0 1 (1)† 0 0

Discontinuation due to adverse event (AE)

6 (6) 5 (5) 9 (10) 5 (6)

Discontinuation for other reasons

4 (4) 8 (8) 6 (7) 7 (8)

*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)

TMC278 25mg qd TMC278 75mg qd TMC278 150mg qd EFV 600mg qd

100

80

60

40

20

0

Vir

olo

gic

res

po

nd

ers

(%, 9

5% C

I)

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

Time (weeks)

90 88 81 84 81 81 81 80 78 2892 90 92 88 88 87 83 81 81 2687 86 83 81 80 79 77 74 75 2384 82 83 79 80 80 80 79 76 27

TMC278 25mg N = 89TMC278 75mg N = 93

TMC278 150mg N = 89EFV 600mg N = 83

93%92%89%

96%

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

100

80

60

40

20

0

0 2 4 8 12 16 20 24 32 40 48

Time (Weeks)

Vir

olo

gic

res

po

nd

ers

(%, 9

5% C

I)

CI = confidence interval

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

81%81%80%77%

Change in log10 plasma VL through 48 weeksM

ean

ch

ang

e in

log

10 V

L (

95%

CI)

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

Time (weeks)

0 2 4 8 12 16 20 24 32 40 48

0.0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

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

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

Mea

n c

han

ge

(95%

CI)

fro

m b

asel

ine

in C

D4

cell

cou

nts

(x

106 /

L)

20

180

140

100

60

0

40

80

120

160

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=89)

Time (weeks)0 2 4 8 12 16 20 24 32 40 48

143145

127125

Most common AEs* at least possibly related to TMC278 or efavirenz

AE preferred term, %

TMC278All TMC278

n=279EFV 600mg

n=8925mgn=93

75mgn=95

150mgn=91

Nausea

Headache

Dizziness

Vomiting

Somnolence

Vertigo

Abnormal dreams

Rash

15.1

6.5

5.4

3.2

2.2

1.1

1.1

0

25.3

11.6

5.3

7.4

3.2

2.1

4.2

0

20.9

5.5

5.5

3.3

4.4

0

0

1.1

20.4

7.9

5.4

4.7

3.2

1.1

1.8

0.4

18.0

7.9

27.0

9.0

10.1

10.1

5.6

5.6

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

NNRTI class effects, any grade, irrespective of causality

AE, system organ class, preferred term, %

TMC278

All TMC278n=279

EFV 600mgn=89

25mgn=93

75mgn=95

150mgn=91

Skin and subcutaneous tissue disorders

All rash*

22.6

5.4

29.5

6.3

29.7

12.1

27.2

7.9

33.7

19.1

Nervous system disorders

Headache

Dizziness

Somnolence

34.4

15.1

10.8

3.2

34.7

22.1

7.4

3.2

30.8

17.6

7.7

4.4

33.3

18.3

8.6

3.6

52.8

15.7

30.3

11.2

Ear and labyrinth disorders

Vertigo 1.1 2.1 0 1.1 11.2

Psychiatric disorders

Insomnia

Depression

Abnormal dreams/nightmares

14.0

6.5

4.3

1.1

12.6

5.3

6.3

6.3

13.2

5.5

3.3

0

13.3

5.7

4.7

2.5

15.7

4.5

2.2

10.1

*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)

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

%

TMC278

All TMC278n=279

EFV 600mgn=89

25mgn=93

75mgn=95

150mgn=91

Any SAE 10.8 10.5 9.9 10.4 9.0

Any grade 3/4 AE 25.8 24.2 24.2 24.7 15.7

Treatment-emergent grade 3/4 laboratory abnormalities

Grade 3/4 laboratory abnormalities, %*

TMC278

All TMC278n=279

EFV 600mgn=89

25mgn=93

75mgn=95

150mgn=91

AST and/or ALT G3

G4

3.3

2.2

2.1

3.2

2.2

2.2

2.5

2.5

1.2

1.2

Creatinine G3

G4

0

0

0

0

1.1

0

0.4

0

0

0

Hemoglobin G3 G4

1.1

1.1

1.1

1.1

0

2.2

0.7

1.5

0

0

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

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

Laboratory data over time

Lipids No TMC278 dose relationship for mean changes in lipid parameters

Endocrine tests No clinically relevant changes in endocrine laboratory parameters

Serum lipids (change from baseline)Mean (SD) TMC278 EFV

Total cholesterol (mg/dL) 5 (±30) 31 (±30)

LDL cholesterol (mg/dL) 0 (±24) 16 (+26)

HDL cholesterol (mg/dL) 5 (±9) 12 (±10)

Ratio total cholesterol/HDL cholesterol

Triglycerides (mg/dL)

- 0.45 (±0.99)

-10 (±79)

- 0.30 (±0.85)

18 (±66)

LDL = low density lipoprotein; HDL = high density lipoprotein

TMC278-C204: 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

Argentina

Dr W Belloso

Dr P Cahn

Dr I Cassetti

Dr A Cassiro

Dr M Losso

Dr S Lupo

Austria

Dr A Rieger

Dr N Vetter

Brazil

Dr C Cunha

Dr C Gonzales

Dr B Grinsztejn

Dr J Madruga

Dr P Rogerio

Dr A Timerman

China

Dr Li Xingwang

Dr Wu Hao

France

Dr P-M Girard

Dr J-M Molina

Dr D Salomon

Dr Y Yazdanpanah

Dr P Yeni

Germany

Dr K Arastéh

Dr G Fätkenheuer

Dr F Goebel

Dr J-A Rump

Mexico

Dr M Santoscoy

Russia

Dr B Gruzdev

Dr O Kozyrev

Dr G Moshkovich

Dr A Pronin

Dr O Romanenko

Dr E Vinogradova

Dr A Yakovlev

South Africa

Dr P Ive

Dr S Miller

Dr L Mohapi

Dr D Steyn

Dr R Wood

Thailand

Dr P Chetchotisakd

Dr K Ruxrungtham

Dr K Supparatpinyo

Dr W Techasatit

Dr A Vibhagool

Uganda

Dr E Katabira

UK

Dr A Pozniak

Dr E Wilkins

US

Dr N Bellos

Dr P Chiliade/ Dr K Sathasivam

Dr C Farthing

Dr J Morales

Dr J Nadler/ Dr B Casanas

Dr P Shalit

Dr M Thompson

Dr A Wilkin

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: