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July 22, 2010

TBR-652 blocks both CCR5 and CCR2, inhibiting HIV replication and reducing inflammation "TBR-652, a dual antagonist or blocker of both the CCR5 and CCR2 cell surface receptors, shows potent activity against HIV and also dampens inflammation, participants heard at the Eighteenth International AIDS Conference this week in Vienna.

"HIV can use two different surface co-receptors – CCR5 and CXCR4 – along with the CD4 receptor to enter T-cells. CCR5 blockers interfere with this process by preventing HIV from attaching to cells. Unlike the sole approved CCR5 antagonist maraviroc (Celsentri), however, TBR-652 also disrupts attachment to CCR2.

"As David Martin from Tobira Pharmaceuticals explained at the conference, CCR2 plays a role in inflammation by binding to monocyte chemoattractant protein 1 (MCP-1), a chemical messenger that summons monocytes and macrophages, types of immune system white blood cells. CCR2 has been studied in relation to a variety of inflammatory diseases including atherosclerosis and metabolic syndrome, and blockade of this receptor appears safe to date.

"A growing body of evidence indicates that low-level persistent HIV infection – even in people on suppressive antiretroviral therapy – can trigger ongoing immune activation and chronic inflammation that contribute to a range of non-AIDS health problems including cardiovascular disease, neurocognitive impairment and non-AIDS-defining cancers. Eventually persistent cell activation can result in immunosenescence, or premature aging and depletion of the immune system.

"Researchers designed a Phase 2 study to test multiple doses of TBR-652 monotherapy, given orally once daily for ten days. A total of 54 participants with confirmed CCR5-tropic HIV were randomly assigned to five groups receiving TBR-652 doses of 25, 50, 75, 100 or 150mg per day; the 100mg group used a slightly different formulation. Two participants in each cohort received placebo."