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Background:  Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components of combination anti-HIV therapy. We need new NNRTI with high potency, an increased genetic barrier to the development of resistance, and convenient dosing. TMC278 (R278474), a diarylpyrimidine (DAPY) derivative, may meet such needs.

Methods:  Virology methods included phenotyping against wild-type and resistant HIV-1, in vitro resistant virus selection, genotyping, and construction of site-directed-mutant strains (SDM). Pharmacokinetics, safety, and tolerability were studied in 3 placebo-controlled, randomized trials in 90 healthy male subjects, using single (12.5 to 300 mg) and multiple (25 to 150 mg once daily for 14 days) oral doses. Concentrations of TMC278 were measured by LC-MS/MS and ex vivo antiviral activity. Safety and tolerability were recorded through vital signs, EKG, clinical laboratory tests, and adverse event reporting.

Results:  TMC278 showed a median EC₅₀ of 0.5 nM (0.19 ng/mL) against wild type HIV-1 and a median CC₅₀ of 8.1 µM. In the presence of 50% human serum, the fold change in EC₅₀ was 9. Among 22 SDM strains with the most prevalent NNRTI mutations, the highest EC₅₀ (2.7 nM, 0.99 ng/mL) was observed against the L100I+K103N double mutant. 89% of > 1500 NNRTI-resistant clinical isolates had an EC₅₀ < 1 0nM for TMC278, as compared with 33% for efavirenz and 0% for nevirapine. No resistant virus was selected in the presence of 40 and 200 nM TMC278 after infection at high MOI. Virus selected at 10 nM TMC278 contained as many as 8 mutations, including L100I, V106I, Y181C, and M230I. TMC278 showed additivity or synergy with current ART. TMC278 was well absorbed, with dose-proportional increases in exposure up to 200 mg. The mean terminal t_1/2 ranged from 34 to 55 hours. At 50 mg, the C_max averaged 247 ng/mL (674 nM) (CV = 12%) and mean AUC (0-¥) was 7720 ng.h/mL (CV = 25%). AUC (0 to 24) increased 2.8-fold over 14 days, suggesting an “effective t_1/2” of 38 hours. LC-MS/MS assay results correlated with ex vivo antiviral activity, suggesting the absence of active metabolites. TMC278 was safe and well tolerated. Headache was the only adverse event occurring more frequently after drug than after placebo. There were no trends of changes in any other safety parameter.

Conclusions:  TMC278 proved to be a potent inhibitor of wild type and resistant HIV-1 and demonstrated an increased genetic barrier to the development of resistance. With its appropriate pharmacokinetics and good tolerability, TMC278 deserves further clinical development as a once-daily oral NNRTI.

Keywords: TMC278; NNRTI; drug candidate