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TBR-652 Inhibits HIV, May Dampen Inflammation

TBR-652, a drug that blocks both CCR5 and CCR2 cell receptors, showed potent antiviral activity against HIV, but did not change most inflammation biomarkers.

HIV uses 2 different surface co-receptors -- CCR5 and CXCR4 -- along with the CD4 receptor to enter T-cells. CCR5 antagonists such as maraviroc (Selzentry) prevent HIV from entering cells by blocking this co-receptor.

Tobira's investigational drug TBR-652 blocks both CCR5 and CCR2, a receptor that binds to monocyte chemoattractant protein 1 (MCP-1, also known as CCL2), a chemical messenger that promotes migration of monocytes and macrophages.

Though not fully understood, CCR2 plays a role in inflammation and has been studied in inflammatory conditions such as atherosclerosis and metabolic syndrome. A growing body of evidence indicates that ongoing immune activation and persistent inflammation may contribute to a range of non-AIDS conditions in people with HIV.

In 2010, researchers presented data from a proof-of-concept study of TBR-652 in HIV positive people at CROI and at the International AIDS Conference in Vienna. Their findings have now been published in the June 1, 2011, Journal of Acquired Immune Deficiency Syndromes.

This double-blind Phase 2 study included 52 participants in the U.S. and 2 in Argentina with confirmed CCR5-tropic (using the CCR5 co-receptor) HIV. Most were men, the average age was about 40 years, and the mean CD4 T-cell count was about 450 cells/mm3. They were treatment-experienced but had never used CCR5 antagonists and had been off all ART for at least 6 weeks at study entry.

Participants were randomly assigned to receive TBR-652 monotherapy at oral doses of 25, 50, 75, 100, or 150 mg per day, or else placebo, once-daily for 10 days. The 100 mg dose group used a different formulation that was later discontinued; these patients -- which included the 2 in Argentina -- were excluded from the efficacy analysis but included in the safety analysis.

At days 1 and 10 the researchers measured HIV RNA and biomarkers associated with inflammation, including MCP-1, high-sensitivity C-reactive protein (hs-CRP), and interleukin 6 (IL-6). Elevated MCP-1 was used as an indicator of effective CCR2 blocking.


  • TBR-652 demonstrated potent anti-HIV activity, significantly greater than that of placebo.
  • Maximum median decreases in HIV RNA from baseline were -0.7, -1.6, -1.8, and -1.7 in the 25, 50, 75, and 150 mg dose groups, respectively, compared with -0.3 in the placebo group.
  • 33%, 71%, 100%, and 75% of patients in respective TBR-652 dose groups achieved viral load reductions of at least 1 log.
  • Participants reached a nadir or lowest HIV viral load after a median of 10-11 days, or just after the last dose.
  • At 10 days levels of MCP-1 increased significantly in the 50 mg and 150 mg dose groups, by about 100 and 300 pg/mL, respectively.
  • The average CRP level decreased, but this was mainly attributable to a single participant with a high baseline level due to acute inflammation.
  • Effects on other immune or inflammation markers including hs-CRP and IL-6 levels were "negligible."
  • CD4 cell count also did not change significantly during the short dosing period.
  • TBR-652 was generally safe and well-tolerated at all doses studied.
  • No severe adverse events or laboratory abnormalities were observed in any TBR-652 dose group, and no participants withdrew due to side effects.

Based on these results, the study authors concluded, "TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested strong CCR2 blockade."

"TBR-652 was generally well tolerated with no dose-limiting adverse events," they continued. "[Pharmacodynamic characteristics] indicate that TBR-652 warrants further investigation as an unboosted, once-daily, oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects."

In their discussion they noted that since the lowest viral loads were observed on average on days 10-11, as treatment was ending, "a true nadir may not have been reached in the 10-day treatment," suggesting viral levels might decline further with longer therapy.

Tobira is now conducted a Phase 2b clinical trial with various substudies to evaluate immunological, cardiovascular, and metabolic parameters, "with the hopes of clarifying their usefulness in predicting inflammatory processes and reducing the risk of inflammatory disease with TBR-652 therapy." Drug interaction studies are also underway to enable construction of a combination regimen with an appropriate TBR-652 dose.

Investigator affiliations: Quest Clinical Research, San Francisco, CA; Private Practice, Houston, TX; Central Texas Clinical Research, Austin, TX; AIDS Research Consortium of Atlanta, Atlanta, GA; Community Research Initiative of New England, Boston, MA; Orlando Immunology Center, Orlando, FL; CIBIC, Rosario, Argentina; AIDS Community Research Initiative of America, Inc.; Tobira Therapeutics, Inc., Princeton, NJ.


J Lalezari, J Gathe, C Brinson, et al. Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naive Subjects. Journal of Acquired Immune Deficiency Syndromes 57(2): 118-125 (abstract). June 1, 2011.