A new drug candidate that blocks both the CCR5 and CCR2 co-receptors demonstrated potent anti-HIV activity and appeared safe and well-tolerated in a small early study, researchers reported at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) taking place this week in San Francisco.
HIV can use two different surface co-receptors – CCR5 and CXCR4 – to enter CD4 cells. CCR5 antagonists such as TBR-652 and maraviroc (Celsentri, Selzentry) are designed to block that co-receptor, and work against virus strains that use only the CCR5 gateway.
TBR-652, being developed by Tobira Therapeutics, was previously shown to be well-tolerated in a study of healthy HIV-negative volunteers.
Phase 1 clinical trials demonstrated the feasibility of once-daily oral dosing. The drug has a half-life in the body of 35 to 40 hours and has favourable pharmacokinetic properties, as reported in a poster at the conference. The current primary formulation has better bioavailability when taken with food.
In the double-blind Phase 2 trial presented at CROI, the first to look at people with HIV, 54 participants with CCR5-tropic virus were randomly assigned to receive TBR-652 monotherapy at different doses.
Successive groups of ten patients received escalating doses of TBR-652 – 25mg, 50mg, 75mg, 100mg or 150mg – once daily for ten days; the 100mg dose was a different formulation. Each dose group had two control participants who received placebo.
Most participants were men, the average age was about 40 years, median viral load ranged from about 10,000 to 40,000 copies/ml, and the mean CD4 cell count was approximately 450 cells/mm3. Participants were treatment-experienced, but had never taken other CCR5 antagonists; at study entry, they had been off treatment for at least six weeks.
By the end of the ten-day dosing period, HIV viral load fell by a median of 0.5 log10 in the 25mg group, 1.3 log10 in the 50mg group, 1.6 log10 in the 75mg group, 1.2 log10 in the 100mg group and 1.5 log10 in the 150mg group.
In comparison, the placebo recipients had only a 0.1 log10 drop.
The largest viral load declines ranged up to 1.8 log10 in the 75mg group. All participants receiving this dose experienced a decrease of at least 1 log10. Of note, in the higher-dose groups viral load continued to decline for up to four days after the last dose.
TBR-652 appeared to be well tolerated overall. One person dropped out of the study early for a reason unrelated to the drug. No serious adverse events, laboratory abnormalities or deaths occurred during the study. The most common side-effects were gastrointestinal symptoms such as nausea and diarrhoea, and body-wide symptoms including headache and fever. No clinically significant heart rhythm changes were seen.
Most side-effects were mild and there was not a consistent dose relationship. Interestingly, while effectiveness was greatest with the 75mg, most adverse events occurred in the two highest dose groups. In fact, no patients in the 75mg group reported any side-effects at all.
None of the participants showed a change from CCR5-tropic to CXCR4-tropic virus, which would allow HIV to use the alternative gateway to enter cells.
There was also no evidence of TBR-652 resistance mutations in this short trial, and prior laboratory studies suggest it has a high barrier to resistance.
With regard to the drug's CCR2 activity, presenter Cal Cohen explained that the CCR2 co-receptor is found on monocytes, dendritic cells and memory T-cells, and it appears to play a role in inflammation; it has been linked to several inflammatory diseases including atherosclerosis and metabolic syndrome. CCR2's primary ligand, or preferred binding partner, is monocyte chemoattractant protein 1 (MCP-1). In this study TBR-652 at all dose levels led to increases in MCP-1 concentrations, with the largest change in the 150mg dose group.
"TBR-652 warrants further investigation as an unboosted, once-daily, oral CCR5 antagonist with potentially important anti-inflammatory effects", the researchers concluded.
Based on the favourable findings from this proof-of-concept trial, Tobira is moving forward with Phase 2b studies of the drug.
Further information
You can view abstract 53 on the official conference website, abstract 598 is not yet available.
You can also view a webcast and slides of this session on the official conference website.
Palleja S et al. Efficacy of TBR 652, a CCR5 antagonist, in HIV-1-infected, ART-experienced, CCR5 antagonist-naive patients. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 53, San Francisco, 2010.
Martin D et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652, a chemokine receptor 5 (CCR5) antagonist, in HIV-infected, antiretroviral (ARV) treatment-experienced, CCR5 antagonist-naive patients. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 598, San Francisco, 2010.