873140, a Novel CCR5 Antagonist, Demonstrates Synergy with Enfuvirtide and Potent Inhibition of Enfuvirtide-resistant R5-tropic HIV-1

CC LaBranche 1, D Davison2, RG Ferris1, GW Koszalka2, JF Demarest1, LR Boone1 and ML Greenberg2
1GlaxoSmithKline, Research Triangle Park, NC, USA, 2Trimeris, Inc, Durham, NC, USA

Development of novel antiretroviral agents is critical in the face of continuing evolution of viruses resistant to currently available therapies. It is essential to characterize the activity of new drugs against resistant viruses as well as their interaction with drugs in current antiviral regimens.

In this study, 873140, a novel spirodiketopiperazine CCR5 antagonist currently in Phase 2/3 clinical trials, was tested in vitro for efficacy against viruses resistant to the only currently approved entry inhibitor, enfuvirtide. 873140 and enfuvirtide were also tested for their antiviral activity in combination.

HIV-1 isolated from patient PBMCs were characterized for susceptibility to enfuvirtide using MAGI and cMAGI target cells. Two R5-tropic, enfuvirtide-sensitive and 4 R5-tropic, enfuvirtide-resistant isolates were subsequently tested for susceptibility to 873140 using the same format.

In separate assays, the ability of the combination of 873140 and enfuvirtide to inhibit HIV-1 Ba-L was evaluated. HOS-CD4-CCR5-LTR-luc cells were pre-incubated with checkerboard titrations of enfuvirtide and 873140 for 1 h at 37°C, then exposed to an inoculum of HIV-1 Ba-L sufficient to produce a signal-to-background of at least 50-fold in the absence of drug.

Results

Both enfuvirtide-sensitive and –resistant R5-tropic HIV-1 isolates were highly susceptible to inhibition by 873140. The median IC50 was 0.28 nM (range 0.17–0.38) for enfuvirtide-sensitive isolates and 0.26 nM (range 0.12–0.32) for enfuvirtide-resistant isolates. For the enfuvirtide/873140 combinations, the average deviation from dose wise additivity was –0.07+/–0.02 (P=0.0009), indicating a slight but statistically significant synergistic interaction between these agents.

Conclusions

The data from these studies predict that 873140 will be effective against enfuvirtide-resistant R5-tropic HIV-1. In addition, these in vitro experiments demonstrate synergism and, importantly, the absence of antagonism between 873140 and enfuvirtide, suggesting that these agents would be suitable for use in combination.

This study suggests that entry inhibitors used in combination may provide new therapeutic approaches for the treatment of ART-experienced individuals.

07/18/05

Reference
CC LaBranche and others. Studies with 873140, a novel CCR5 antagonist, demonstrate synergy with enfuvirtide and potent inhibition of enfuvirtide-resistant R5-tropic HIV-1 (poster). XIV International HIV Drug Resistance Workshop IC Report: Basic Principles and Clinical Implications. June 7-11, 2005. Québec City, Québec, Canada. [Antiviral Therapy 2005; 10:S73]

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