TBR-652

TBR-652 is a CCR5 antagonist being developed by Tobira Therapeutics. The drug has a half-life in the body of 35 to 40 hours. Phase I clinical trials have demonstrated the feasibility of once-daily oral dosing and safety in HIV-negative volunteers.

In a double-blind phase II trial, 54 HIV-positive participants with CCR5-tropic virus received escalating doses of TBR-652 – 25mg, 50mg, 75mg, 100mg or 150mg – once daily for ten days.¹ The drug was given as monotherapy. Each dose group had two control participants who received placebo.

By the end of the ten-day dosing period, HIV viral load fell by a median of 0.5 log₁₀ in the 25mg group, 1.3 log₁₀ in the 50mg group, 1.6 log₁₀ in the 75mg group, 1.2 log₁₀ in the 100mg group and 1.5 log₁₀ in the 150mg group, compared to a 0.1 log₁₀ drop with placebo.

The largest viral load declines ranged up to 1.8 log₁₀ in the 75mg group. All participants receiving this dose experienced a decrease of at least 1 log₁₀. In the higher-dose groups, viral load continued to decline for up to four days after the last dose.

No serious adverse events, laboratory abnormalities or deaths occurred during the study. The most common side-effects were gastrointestinal symptoms such as nausea and diarrhoea, and body-wide symptoms including headache and fever.Most side-effects were mild and there was not a consistent dose relationship. None of the participants showed a change from CCR5-tropic to CXCR4-tropic virus, which would allow HIV to use the alternative gateway to enter cells.

There was also no evidence of TBR-652 resistance mutations in this short trial, and prior laboratory studies suggest it has a high barrier to resistance.

TBR-652 also blocks the CCR2 co-receptor found on monocytes, dendritic cells and memory T-cells, which appears to play a role in inflammation. Results from the ten-day trial confirm that TBR-652 is active as a CCR2 blocker as well as a CCR5 blocker.² This suggests a possible anti-inflammatory role which will be a subject of ongoing investigation.