MILESTONES

MILESTONE 5 fomivirsen for the treatment of CMV retinitis in individuals with AIDS. In a pivotal phase III RCT, patients with First antisense drug is approved newly diagnosed CMV retinitis were randomly allocated to immediate intravitreal fomivirsen treatment or with fleeting success treatment deferral until progression. Median time to progression was Following the initial reports and (EMA; formerly the EMEA) for the 71 days in the immediate treatment characterization of gene silencing same indication in 1999. group, versus 13 days in the deferred …the success through endogenous and exogenous Fomivirsen is a synthetic treatment group. Progression after of [this drug] antisense RNAs, the first antisense 21‑nucleotide phosphorothioate treatment cessation occurred in oligonucleotide drug, fomivirsen, oligodeoxynucleotide designed to 44% of patients receiving immediate provided proof- received regulatory approval from be complementary to a sequence treatment, versus 70% of patients in of-concept of the United States Food and Drug in CMV mRNAs encoding the the deferred treatment group. Two the clinical Administration (FDA) in 1998. This major immediate-early region 2 additional RCTs demonstrated the promise of agent was indicated for the treatment proteins, which are essential for comparable efficacy of an intensive treatments of cytomegalovirus (CMV) retinitis CMV replication. In line with this and less-intensive regimen of intra- — a serious infection of the retina antisense mechanism of action, early vitreal fomivirsen for the treatment based on that can rapidly lead to blindness preclinical characterization revealed of CMV retinitis that had not been antisense oligo- — in carriers of human immuno­ that fomivirsen potently and selec- controlled by other drugs. nucleotides… deficiency virus (HIV) exhibiting tively disrupted CMV replication in However, despite the initial enthu- acquired immune deficiency syn- a dose-dependent manner in vitro, siasm and unmet clinical need in the drome (AIDS), who were intolerant providing the first indication of its late 1990s, the success of fomivirsen of, or had contraindications to, other efficacy. was ultimately fleeting. The drug treatments or were insufficiently Regulatory approval was largely was withdrawn by the FDA in 2001, responsive to previous treatments. based on three prospective rand- owing to the success of highly active Fomivirsen was subsequently omized controlled trials (RCTs) antiretroviral therapy in reducing the granted marketing authorisation led by the Vitravene Study Group, incidence of opportunistic infections by the European Medicines Agency which demonstrated the efficacy of in individuals with HIV in the early 2000s, which undermined demand for fomivirsen. The EMA followed suit in 2002, when the manufacturer (Novartis) voluntarily withdrew the drug from the market due to low demand. Nevertheless, the success of fomi­ virsen provided proof‑of‑concept of the clinical promise of treatments based on antisense oligonucleotides, which was undoubtedly valuable for the next wave of antisense drug approvals, beginning in 2013 with the FDA approval of mipomersen (an antisense oligonucleotide inhibitor of apolipoprotein B) for the treatment of homozygous familial hypercholesterolemia. Conor A. Bradley, Senior Editor, Nature Reviews Cross-Journal Team

FURTHER READING Drug Approval Package: Vitravene (US FDA, 2002); https://go.nature. com/2kfsM3N | Vitravene (EMA, 2002); https://go. nature.com/2kJcOze | Vitravene Study Group. A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am. J. Ophthalmol. 133, 467–74 (2002) | Vitravene Study Group. Randomized dose- comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. Am. J. Ophthalmol. 133, 475–83 (2002). Credit: Westend61 GmbH / Alamy Stock Photo Stock Alamy / GmbH Westend61 Credit:

NATURE MILESTONES | ANTISENSE RNA DECEMBER 2019 | S9