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TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials

TTCA0062-07262-1. TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials. R Haubrich , M Schechter, S Walmsley, M Peeters, M Janssens, G De Smedt on behalf of the DUET-1 and DUET-2 study groups.

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TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials

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  1. TTCA0062-07262-1 TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials R Haubrich, M Schechter, S Walmsley, M Peeters, M Janssens, G De Smedt on behalf of the DUET-1 and DUET-2 study groups Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  2. TTCA0062-07262-2 DUET: Study Design • Inclusion criteria • plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks • ≥1 NNRTI mutations,‡ current or documented historical • ≥3 primary PI mutations • sites: Thailand, Australia, Europe and the Americas 24-week primary analysis TMC125 + BR* Randomized Placebo + BR* *All patients received a background regimen of DRV/r plus NRTIs and optional enfuvirtide ‡From extended list of NNRTI mutations; BR = background regimen; DRV/r = darunavir with low-dose ritonavir; RAM = resistance-associated mutation Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  3. TTCA0062-07262-3 Baseline Characteristics and Treatment Duration Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  4. TTCA0062-07262-4 Overview of Adverse Events • AEs leading to death were not reported in more than one patient except for pneumonia and sepsis (n=2 each) in the placebo group • None of the deaths in the TMC125 group were considered related to TMC125 *excluding injection site reactions; §p=0.0001 vs placebo; AE = adverse event Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  5. TTCA0062-07262-5 Grade 3 and 4 Adverse Events *excluding injection site reactions and grade 3/4 laboratory abnormalities reported as AEs Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  6. TTCA0062-07262-6 Rash • In the TMC125 group: • Early onset: median 12 days • Limited duration: median 11 days • Low severity: most mild to moderate; 1.3% grade 3, none grade 4 • mostly maculopapular; no mucosal involvement • Infrequently led to discontinuation: 2.2% of patients (0% with placebo) • most resolved with continued treatment • Clinical associations with rash • No association with baseline CD4 cell count • No increased risk with prior NNRTI-related rash Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  7. TTCA0062-07262-7 Incidence of Rash by Gender • Higher incidence in women: 28% vs 16% in men • No clear difference in severity or discontinuations between genders Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  8. TTCA0062-07262-8 Placebo group (n=604) Incidence and Prevalence of Rash (Any Type) by Treatment Group TMC125 group (n=599) Incidence Prevalence 10 8 6 4 2 0 10 8 6 4 2 0 Incidence (%) Prevalence (%) 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Week Week Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  9. TTCA0062-07262-9 Nervous System* • Similar incidence to placebo: 15% in TMC125 group versus 18% in placebo group (p=0.09) • Low severity: mostly grade 1 and 2 • Did not lead to discontinuation: none in TMC125 group and 1.0% of placebo group *Includes only nervous system events associated with the use of approved NNRTIs Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  10. TTCA0062-07262-10 Psychiatric Disorders • Similar incidence to placebo: 13% in TMC125 group versus 15% in placebo group (p=0.3) • Low severity: mostly grade 1 and 2 • Infrequently lead to discontinuation: 1 patient (0.2%) in each group • No increased risk in patients with a history of psychiatric disorders • Abnormal dreams/nightmares in 5 patients (0.8%) in each group and no episodes of hallucinations, suicidal ideation or manic symptoms with TMC125 Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  11. TTCA0062-07262-11 Hepatic AEs and Laboratory Abnormalities TMC125 group Placebo group AST ALT 20 0 –20 –40 20 0 –20 –40 Change from baseline (U/L) 0 8 16 24 32 40 48 0 8 16 24 32 40 48 Week Week ALT = alanine aminotransferase; AST = aspartate aminotransferase Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  12. Abstract 1210 TTCA0062-07262-12 Treatment-emergent Laboratory Abnormalities ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  13. Lipid Changes over Time TTCA0062-07262-13 TMC125 group Placebo group HDL LDL calculated Change from baseline (mg/dL) Triglycerides Total cholesterol/HDL Change from baseline (mg/dL) Week Week HDL = high density lipoprotein; LDL = low density lipoprotein Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  14. TTCA0062-07262-14 Placebo group Hospitalizations TMC125 group 1700 16% p=0.0031 1105 11% Patients hospitalized at least once by 24 weeks (%) Cumulative days hospitalized by 24 weeks Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

  15. TTCA0062-07262-15 Safety Conclusions from DUET • Assessing safety/ tolerability of this new agent in a complex background was facilitated by the placebo-controlled design • Safety and tolerability of TMC125 was similar to placebo • Rash, the only AE to occur more frequently with TMC125 • generally mild to moderate • often resolved with continued treatment • associated with low discontinuation (2% versus 0% with placebo) • Overall, most AEs were of low severity and infrequently led to discontinuation • 6% vs 4% in the TMC125 vs placebo groups • TMC125 was not associated with any increase in laboratory abnormalities, including hepatic and lipid parameters • TMC125 provides a tolerable new option for treatment-experienced patients • not associated with common NNRTI side effects Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

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