Fomivirsen - a phosphorothioate oligonucleotide for the treatment of CMV retinitis

Abstract

Fomivirsen is a 21-nucleotide phosphorothioate oligonucleotide which, when injected into a human eye, is capable of inhibiting CMV retinitis. Its mode of action is consistent with an antisense mechanism. Prior to human trials, fomivirsen was tested in a number of in vitro cell lines and was found to inhibit CMV replication in a dose-dependent manner with a mean 50% inhibitory concentration between 0.03 and 0.2 microM. Intravitreal drug clearance studies have revealed first-order kinetics with a half-life in the rabbit of 62 hours. In a clinical trial of patients with newly diagnosed CMV retinitis receiving 165 mg per injection, time to progression was interpolated to 71 days with 44% of the patients remaining on treatment for over one year. In patients who failed other anti-CMV treatments, the interpolated time to progression was 91 days when receiving 330 mg per injection. No systemic absorption of the drug could be detected. Reported adverse events have been for the most part mild to moderate in intensity and either resolved spontaneously or were treatable with topical medications. Locally administered fomivirsen effectively inhibits CMV retinitis using a mode of action which is complementary to existing DNA polymerase inhibitors.