AEGiS-15IAC: A novel CCR5 antagonist, 873140, exhibits potent in vitro anti-HIV activity.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

A novel CCR5 antagonist, 873140, exhibits potent in vitro anti-HIV activity.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1231)

Demarest J, Shibayama S, Ferris R, Vavro C, St Clair M, Boone L
GlaxoSmithKline, Research Triangle Park, NC, United States

BACKGROUND: 873140 is an orally bioavailable CCR5 antagonist that binds specifically to human CCR5 with prolonged receptor occupancy demonstrated both in vitro and in vivo. 873140 was safe and well tolerated in seven day multiple dose studies of healthy volunteers. The in vitro anti-HIV activity of 873140 was evaluated with laboratory and clinical isolates.

METHODS: Activated peripheral blood mononuclear cells (PBMC) isolated from multiple donors (pools or individual samples) were infected with laboratory strains (BaL, ADA) or R5-tropic clinical isolates representing different HIV-1 clades. Antiviral potency was determined with serial dilutions of 873140. The effect of donor PBMC variability on 873140 anti-HIV potency was evaluated with different R5-tropic isolates and the laboratory strain BaL.

RESULTS: The mean IC50 for 873140 tested against a panel (n=22) of clade B R5-tropic clinical isolates was 0.3 nM (95% C. I. 0.17 to 0.51 nM). For non Clade B viruses (n=13), the mean IC50 was 0.33 nM (95% C. I. 0.11 to 1.0 nM). BaL sensitivity to 873140 evaluated in different donor PBMCs (n=36) showed a mean IC50 value of 2.3 nM (95% C. I. 1.7 to 3.1 nM). Likewise, limited variability in 873140 anti-HIV activity was observed against different R5-tropic clinical isolates tested in PBMC from multiple donors. In addition, 873140 showed additive or synergistic activity when tested in combination with currently approved reverse transcriptase (RT) or protease (Pr) inhibitors. Conclusion 873140 exhibited potent antiviral activity in vitro in the subnanomolar range for the majority of clinical isolates tested. The anti-HIV potency was comparable across HIV-1 clades and showed minimal variation across different PBMC donors. 873140 did not antagonize the antiviral activity of other antiretroviral agents in the RT or Pr classes. These data support further evaluation of 873140 in HIV-infected individuals.

Keywords: AEGIS, Receptors, CCR5, Acquired Immunodeficiency Syndrome, HIV Seropositivity, HIV-1, Anti-HIV Agents, RNA-Directed DNA Polymerase, Reverse Transcriptase Inhibitors, Anti-Retroviral Agents, Antiviral Agents, Humans, In Vitro

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WeOrA1231