Background:  Maraviroc (MVC) is the first-in-class anti-HIV CCR5 antagonist, with demonstrated clinical efficacy and convenient twice daily dosing. Resistance to MVC in vitro and in the clinic can occur via envelope mutations that enable HIV entry through recognition of MVC-bound receptor. We have previously shown that MVC-resistant virus generated in vitro can be inhibited by antagonists from structurally related chemical series. We set out to identify an inhibitor with the pharmacokinetic and safety credentials of a second-generation clinical candidate and activity against MVC-resistant HIV.

Methods:  Chemical lead series were evaluated for activity against CCR5 and other receptors, inhibition of HIV envelope-mediated fusion, and efficacy against lab-adapted and envelope-pseudotyped viruses. Extensive preclinical pharmacokinetic and safety studies preceded evaluation of the lead compound, PF-232798, in healthy human volunteers.

Results:  PF-232798 is a CCR5 antagonist (IC₅₀ 5.9 to 6.6 nM) against a range of chemokine ligands). It blocks envelope-mediated cell-cell fusion (IC₅₀ 32 pM, 95%CI 25 to 40 pM), and inhibits replication of lab-adapted viral isolates in peripheral blood leukocyte (PBL) culture (EC₉₀ 2.0 nM, 95%CI 1.5 to 2.6 nM) and primary origin envelop-recombinant strains (n = 18, cross-clade panel) in the PhenoSense assay (EC₉₀ 51 nM, 95%CI 36 to 73 nM). When tested against in vitro generated MVC-resistant isolates, PF-232798 has less than a 50% drop in maximal inhibition and EC₅₀ compared to the wild type virus. Structural modelling based on data from CCR5 site-directed mutagenesis studies, indicates that PF-232798 binds to a receptor trans-membrane pocket, in a way similar to MVC but with different interactions at the ECL2 hinge region. PF-232798 was well tolerated in healthy human volunteers at single oral doses of up of 750 mg. Pharmacokinetics studies highlight that a once daily dose of 250 mg should be sufficient to provide trough free plasma concentrations in excess of 15-fold the antiviral EC_90.

Conclusions:  PF-232798 is an investigational second-generation CCR5 antagonist with broad antiviral efficacy and activity against MVC-resistant strains in vitro. The low dose projected for clinical efficacy, coupled with good toleration in healthy volunteers are particularly encouraging. Further studies to evaluate the clinical utility of PF-232798 are ongoing.