TMC278 (rilpivirine), an investigational next-generation NNRTI, demonstrates long-term efficacy and ...
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M Santoscoy, 1 P Cahn, 2 C Gonsalez, 3 W Hao, 4 A Pozniak, 5 P Shalit, 6 S Vanveggel, 7 K Boven 8 PowerPoint PPT Presentation


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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 Boven 8

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M Santoscoy, 1 P Cahn, 2 C Gonsalez, 3 W Hao, 4 A Pozniak, 5 P Shalit, 6 S Vanveggel, 7 K Boven 8

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Tmc278 rilpivirine an investigational next generation nnrti demonstrates long term efficacy and tolerability in arv na

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,4A 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 You’an 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.


Tmc278 a next generation nnrti with potent anti hiv 1 activity

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-C204study 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


Tmc278 c204 study design

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 randomization1:1:1:1

ARV-naïve patients (N=368)

HIV RNA5,000 copies/mL

EFV 600mg qd + 2 NRTIsN=89

TMC278 25mg qd + 2 NRTIsN=93

TMC278 75mg qd + 2 NRTIsN=95

TMC278 150mg qd + 2 NRTIsN=91

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


Demographic and baseline characteristics

Demographic and baseline characteristics

*Median values

‡n=88 for EFV 600mg


Tmc278 high response rate and sustained virologic response over 96 weeks similar to efv

TMC278: high response rate and sustained virologic response over 96 weeks similar to EFV

HIV-1 RNA <50 copies/mL to Week 96 (ITT-TLOVR algorithm)

TMC278 25mg qd (n=93)TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)EFV 600mg qd (n=89)

100

80

60

40

20

0

76%

72%

71%

71%

Virologic responders (%, 95% CI)

024812162024324048566472808896

Time (weeks)

CI = confidence interval


Tmc278 potent antiviral efficacy at week 48 sustained to week 96

TMC278: potent antiviral efficacy at Week 48 sustained to Week 96

AE = adverse event*Patients with loss of virologic response, patients who never achieved confirmed viral load <50 copies/mL or patients who discontinued before reaching Week 96 due to lack of virologic efficacy


Tmc278 continued cd4 increases through week 96

TMC278: continued CD4 increases through Week 96

Hatched bars: Week 48

Solid bars: Week 96

122

146

145

172

143

159

127

160

200

150

Mean change in CD4 cell countfrom baseline (cells/mm3, 95% CI)

100

50

0

TMC278 25mg qd (n=93)

TMC278 75mg qd (n=95)

TMC278 150mg qd (n=91)

EFV 600mg qd (n=88)

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


Tmc278 rilpivirine an investigational next generation nnrti demonstrates long term efficacy and tolerability in arv na

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)


Tmc278 rilpivirine an investigational next generation nnrti demonstrates long term efficacy and tolerability in arv na

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


Incidences of rash nervous system and psychiatric related aes were lower with tmc278 than with efv

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 dapsone‡p<0.01 vs EFV; §p<0.05 vs EFV (Fisher’s exact test)


Increases in lipid parameters were lower with tmc278 than with efv

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 = triglycerides*p<0.01, ‡p=0.19 for EFV vs TMC278 (nonparametric Wilcoxon rank sum test, post-hoc analysis)


Additional investigations

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


Conclusions

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


Acknowledgements

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:


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