Background:  TBR‑652, a promising CCR5 antagonist, was well tolerated by healthy volunteers. Phase 1 PK showed the feasibility of once-daily dosing in HIV-1-infected patients. This is the first report of TBR-652 in HIV-1-infected patients.

Methods:  This was a double-blind, placebo-controlled, randomized (4:1 TBR-652:placebo), dose-escalating study to assess the PK/PD of TBR‑652 monotherapy given orally once daily for 10 days in HIV‑1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naive patients. 10 patients/dose level received 25, 50, or 75 mg TBR-652 or placebo in one of 2 dose formulations. Blood was collected at pre-specified intervals for HIV-1 RNA and PK assessments. The relationship between plasma TBR‑652 and HIV-RNA levels was modeled using population PK/PD analysis methods in Phoenix WinNonlin. A 2-compartment model was used to model the PK of TBR‑652. An effect compartment model combined with a sigmoidal E_max model was used to model HIV-1 RNA data over 40 days.

Results:  Mean log₁₀ viral load change from baseline on Day 11 for placebo, 25 mg, 50 mg, and 75 mg TBR-652 were -0.04, -0.66, ‑1.11, and -1.5, respectively. Additionally, the percentage of patients achieving a greater than 1.0 log₁₀ decline from baseline on Day 11 for placebo, 25 mg, 50 mg, and 75 mg TBR-652 were 0%, 33%, 71%, and 100%, respectively. The baseline (E₀) and maximum antiviral effect of TBR-652 (E_max) determined with the PK/PD model were 4.37 and 1.87 log₁₀, respectively. A steep concentration-effect relationship was observed, with effective concentrations of TBR-652 resulting in 50% of inhibition (EC₅₀) of 15.3 ng/mL and a sigmoid factor of 2.70.

Conclusions:  TBR-652 demonstrates good PK/PD properties at the dose levels evaluated. Data showed a clear dose- and exposure-response relationship. Dose levels of 100 and 150 mg QD for 10 days are being evaluated, and the results of all 5 dose levels will be reported at the meeting.