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TMC-125: efficacy & safety in highly resistant patients
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Reported by Jules Levin
EACS
Dublin, Nov 18, 2005
J Nadler presented these study results at EACS in Dublin. TMC-125 is the first NNRTI to show significant activity & safety in patients with prior failure to efavirenz and nevirapine. C223 is a randomized, dose-finding, US study of TMC125 in 199 patients with documented NNRTI resistance and ≥3 primary PI mutations (median 4). Subjects were randomized to receive TMC125 (400 mg or 800 mg bid) with an investigator selected background, or a standard-of-care control regimen. Primary endpoint was change in viral load from baseline at week 24.
Median baseline viral load was 4.7 log10 copies/ml and CD4 count 99 cells/mm3. The study patients are highly treatment experienced with 60% of the patients having 2 or more NNRTI drug resistance mutations & 50% of the patients having 4 or more primary protease inhibitor drug resistance mutations. At baseline patients were 41-fold resistant to efavirenz & 61-fold resistant to nevirapine, and 1.6 fold resistant to TMC-125. At week 24, mean changes in HIV-1 RNA for TMC125 400 mg, 800 mg and control were -1.04, -1.18 and -0.19 log10, respectively, and 36%, 42% and 8% had a >1 log10 decrease (ITT NC=F). HIV-1 RNA < 50 copies/ml were 21%, 18% and 8%. Mean CD4 cell increases were 47, 48 and 10 cells/mm3. Both TMC125 arms were statistically superior to control for change in viral load at week 24, with no significant differences between doses for efficacy or tolerability. Grade 3/4 AEs (all causes) were reported in 17% of patients on TMC125, with 14% discontinuing due to AEs. Rash was seen in 20% on TMC125 with 3% discontinuations.
In the control arm, 95% of patients discontinued treatment, 75% for virologic failure (VF). VF on TMC125 400 and 800 mg was 6% and 5%, respectively.
Author Conclusion
TMC125 was generally well tolerated and showed potent efficacy in heavily-pre-treated patients with substantial NNRTI and PI resistance. These data provide further evidence that TMC125 may be used to treat patients with prior NNRTI failure. TMC125 showed significant, clinically relevant and sustained efficacy in
heavily pre-treated patients with substantial NNRTI and PI resistance. Due to a high incidence of early discontinuation in the active control group
(primarily due to virologic failure) the safety comparison in this study was
confounded. No undue safety concerns with TMC125 were noted. TMC125 is the first NNRTI to show significant activity in patients with prior NNRTI failure. TMC125 has the potential to be the first NNRTI to enable sequencable use of
this drug class. A new 200 mg bid formulation (2 tablets twice daily), which provides comparable exposures to the 800 mg bid formulation used in this trial, has been selected for Phase III clinical studies. TMC125 Phase III clinical studies have now commenced
"Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223"
Jerald Nadler reported the study results from this trial in Dublin today.
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