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 HIV and Hepatitis.com Coverage of the
XVIII International AIDS Conference
(AIDS 2010)  July 18 - 23, 2010, Vienna, Austria
Investigational HIV Drug TBR-652 Reduces Viral Replication and May Dampen Inflammation

SUMMARY: Tobira Pharmaceuticals' TBR-652, an experimental drug that blocks both the CCR5 and CCR2 cell surface receptors, has the dual effect of inhibiting HIV and affecting a biomarker associated with inflammation, according to data presented at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna. TBR-652 was generally well-tolerated and a Phase 2b clinical trial is planned for early next year.

By Liz Highleyman


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 new 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 attracts monocytes and macrophages. Though its function is not fully understood, CCR2 plays a role in inflammation and has been studied in relation to inflammatory conditions including atherosclerosis and metabolic syndrome. To date, researchers have seen no major safety concerns with blocking CCR2.

Investigators presented the first data from a pilot study of TBR-652 in people with HIV at this year's Retrovirus conference (CROI). The recent presentation at AIDS 2010 focused more on the inflammation-modulating effects of the drug. A growing body of evidence indicates that ongoing immune activation and chronic inflammation due to persistent HIV infection -- even in people on suppressive antiretroviral therapy -- may contribute to a range of non-AIDS conditions including cardiovascular disease and neurocognitive impairment.

In this Phase 2 study, 54 participants with confirmed CCR5-tropic (using the CCR5 co-receptor) HIV were randomly assigned to receive TBR-652 monotherapy at doses of 25, 50, 75, 100 or 150 mg per day, or else placebo, for 10 days (the 100 mg group used a different formulation than the rest).

Most participants (nearly 90%) were men, the average age was about 40 years, the median HIV viral load was approximately 30,000 copies/mL, and the mean CD4 cell count was about 450 cells/mm3 (all had at least 250 cells/mm3). Participants were treatment-experienced but had never used other CCR5 antagonists and had not taken antiretroviral drugs for at least the past 6 weeks.

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

Results
TBR-652 demonstrated potent activity against HIV.
Maximum decreases in HIV RNA from baseline were -0.7, -1.7, -1.8, -1.4, and -1.7 in the 25, 50, 75, 100, and 150 mg dose groups, respectively, compared with -0.3 in the placebo group (all statistically significant).
Levels of MCP-1 increased by about 50, 100, 30, 80, and 300 pg/mL, respectively, in the 5 TBR-652 dose groups, but did not change in the placebo group (significant for the 50, 100, and 150 mg groups).
The average CRP level decreased, but this was mainly attributable to a single participant with a high baseline level due to acute inflammation.
IL-6 was undetectable in all participants, suggesting that the lower limit of the test may have been too high.
TBR-652 was generally safe and well-tolerated.
1 person discontinued the study early for a reason other than adverse events.
There were no severe adverse events or significant laboratory abnormalities in any of the TBR-652 dose groups.
The most common side effects were headache, diarrhea, nausea, and fatigue.

Based on these results, the researchers concluded, "TBR 652 is a potent inhibitor of CCR5-tropic HIV-1 replication" and "demonstrated potent CCR2 inhibition," with a "favorable and predictable pharmacokinetic profile."

Following the presentation, some attendees expressed concern that TBR-652 might interfere with immune response in ways that increase the risk of infections, as suggested in some prior animal and human studies of blocking CCR-2, but presenter David Martin of Tobira said no increase in infection rates has been observed so far in human trials of TBR-625.

Tobira expects to start a Phase 2b trial in early 2011, which will include various sub-studies to evaluate the effects of TBR-652 on immunological, cardiovascular, and metabolic parameters.

Investigator affiliations: Tobira Therapeutics, Inc., Princeton, NJ; Private Practice, Houston, TX; AIDS Research Consortium of Atlanta, Atlanta, GA; Community Research Initiative of New England, Boston, MA; Orlando Immunology Clinic, Orlando, FL; Central Texas Clinical Research, Austin, TX; Whitman Walker/Elizabeth Taylor Clinic, Washington, DC; CIBIC, Rosario, Argentina; AIDS Community Research Initiative of America (ACRIA), New York, NY; Light Source Medical Group, Los Angeles, CA.

8/3/10

Reference
DE Martin, S Palleja, J Gathe, and others. TBR-652, a potent dual CCR5/CCR2 antagonist in Phase 2 development for treatment of HIV infection. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract MOAB0104.


 

 

 

 

 

 

 

 

 

 

 



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