TBR-652, a potent dual chemokine receptor 5/chemokine receptor 2 (CCR5/CCR2) antagonist in phase 2 development for treatment of HIV infection
Presented by David E. Martin (United States).
D.E. Martin1, S. Palleja1, J. Gathe2, M. Thompson3, C. Cohen4, E. De Jesus5, C. Brinson6, R. Elion7, J. Galindez8, J. Ernst9, P. Ruane10, R. Ogden1, R. Driz1, J. Sapirstein1
1Tobira Therapeutics, Inc., Princeton, United States, 2Private Practice, Houston, United States, 3AIDS Research Consortium of Atlanta, Atlanta, United States, 4Community Research Initiative of New England, Boston, United States, 5Orlando Immunology Clinic, Orlando, United States, 6Central Texas Clinical Research, Austin, United States, 7Whitman Walker/Elizabeth Taylor Clinic, Washington, United States, 8CIBIC, Rosario, Argentina, 9AIDS Community Research Initiative of America (ACRIA), New York, United States, 10Light Source Medical Group, Los Angeles, United States
Background: TBR-652, a potent, dual CCR5/CCR2 antagonist, was well tolerated by healthy volunteers in Phase 1 studies that showed the feasibility of once-daily dosing. The first study of once-daily TBR‑652 in 54 HIV-1-infected patients is reported here.
Methods: This was a randomized (4:1 to TBR‑652), double-blind, placebo-controlled, dose-escalating study to assess the antiviral activity, safety, and tolerability of TBR‑652 monotherapy given orally once daily (QD) for 10 days in HIV‑1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve, CCR5-positive patients. Patients received 25, 50, 75, 100, or 150 mg TBR‑652 or placebo. Antiviral activity was monitored by changes in HIV‑1 RNA, and CCR2 activity was measured by changes in MCP‑1 levels from Baseline.
Results: TBR‑652 monotherapy was generally well tolerated for 10 days at all dose levels, with predominantly grade 1 AEs, no serious AEs, no deaths, and only 1 discontinuation during dosing (not related to study drug).
[Viral Load and MCP-1 Results]
|Dose Group||Median ΔHIV-1 RNA, Day 11||Median ΔMCP 1, Day 10|
| ||(log10 copies/mL)||n||(pg/mL)||n|
|25 mg QD||-0.5||9||25.0||9|
|50 mg QD||-1.3||7||56.0||7|
|75 mg QD||-1.6||8||36.0||7|
|100 mg* QD||-1.2||10||74.5||8|
|150 mg QD||-1.5||8||322.0||8|
|*Different tablet formulation|
Conclusions: TBR‑652 was generally safe and well-tolerated. There was potent antiviral activity and a significant effect on HIV‑1 RNA and MCP‑1 levels. This confirms that TBR-652 is a potent CCR5/CCR2 antagonist. To determine the clinical relevance of this finding, further investigation of TBR‑652 is warranted in longer duration studies.
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