TBR-652 Inhibits HIV, May Reduce Inflammation

TBR-652, being developed by Tobira Pharmaceuticals, is a new CCR5 antagonist entry inhibitor that also blocks CCR2, another surface receptor on certain white blood cells. CCR2, which binds to monocyte chemoattractant protein 1 (MCP-1), appears to play a role in inflammation and has been linked to inflammatory conditions such as atherosclerosis.

At last February's CROI, Cal Cohen gave the first presentation on the drug, reporting that it had potent antiviral activity and it appeared to be safe and well-tolerated in a Phase II proof-of-concept trial (abstract 53).

The study included 54 HIV positive participants, mostly men, with exclusively CCR5-tropic virus and an average CD4 cell count of about 450 cells/mm3. They were treatment-experienced but had been off ART for at least six weeks and had never used another CCR5 antagonist. Patients were randomly assigned to receive TBR-652 at doses of 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg per day, or else placebo, for ten days.

By the end of the treatment period, TBR-652 at doses of 50 mg and higher suppressed HIV by at least 1 log (up to 1.8 log in the 75 mg dose group). The drug was well-tolerated with no severe adverse events, serious laboratory abnormalities, or deaths. The most common adverse events were gastrointestinal and flu-like symptoms.

At AIDS 2010, David Martin from Tobira reported further data from the same study, with an emphasis on TBR-652's inflammation-modulating effects (abstract MOAB0104). MCP-1 levels increased in all TBR-652 dose groups (up to 300 pg/mL in the 150 mg arm) -- which the researchers used as an indicator of effective CCR2 receptor blocking -- but remained stable in the placebo group.

C-reactive protein (an inflammation biomarker) decreased on average, but this was mainly attributable to a single participant with a high baseline level. Interleukin 6 (IL-6) was undetectable in all participants, suggesting that the test may not have been sensitive enough.

Some audience members expressed concern that TBR-652 might interfere with immune response in ways that could increase risk of infections, as seen in prior animal and human studies of CCR2 blocking. Martin said no such increase in infections had been observed in TBR-625 trials so far. Tobira announced that it plans to start a Phase IIb clinical trial in early 2011 that will evaluate the effects of TBR-652 on immunological, cardiovascular, and metabolic parameters.

Liz Highleyman (liz@black-rose.com) is a freelance medical writer based in San Francisco.