Fomivirsen

Description

Fomivirsen sodium (Vitravenes, Isis Pharmaceuticals, Carlsbad, CA, and Novartis Pharmaceuticals, Switzerland), is a 21-base phosphorothioate DNA antisense oligonucleotide designed to be complimentary to a cytomegalovirus (CMV) messenger RNA (mRNA) which encodes for the major immediate early region (IE2) proteins of this virus. It is the first in its class of highly specific and novel therapeutics, antisense oligonucleotides. The sequence of the fomivirsen oligonucleotide is 5u-GCG TTT GCT CTT CTT CTT GCG-3u (where G = guanosine, C = cytosine, T = thymidine). Fomivirsen sodium intravitreal injectable (fomivirsen) is a white to off-white, hygroscopic, amorphous powder. Fomivirsen is available as a sterile, aqueous, preservative-free and bicarbonate-buffered solution.

Indications

Fomivirsen (Vitravene), an anti-CMV agent, is the first antisense oligonucleotide to be approved by the U. S. Food and Drug Administration (FDA) as an antiviral therapy. Fomivirsen is an oligonucleotide complementary to the major immediate early region 2 (IE2) of CMV mRNA. By binding to IE2 mRNA, fomivirsen prevents its translation to protein and thereby blocks viral replication. Because this mechanism of action is different from that of other antiviral agents, crossresistance with other drugs used to treat CMV is unlikely.

Pharmaceutical Applications

An antisense oligonucleotide, 21 bases in length, representing the mirror image of a region of mRNA coding for a regulatory protein of CMV. It is administered as the sodium salt by intraocular injection. Experiments in monkeys suggest that it has a very long elimination half-life (c. 3 days). Because of its unique mode of action fomivirsen retains activity against strains of CMV resistant to other antiviral agents. Side effects commonly include ocular inflammation, which is responsive to topical steroids, and raised intraocular pressure.

Biological Activity

Ocular disposition and clearance of fomivirsen following an intravitreal injection has been studied in rabbits and cynomolgus monkeys. When fomivirsen was administered by a single intravitreal injection in rabbits it was cleared rapidly from the vitreous as a result of metabolism of the parent drug. Clearance of 14C-labeled fomivirsen from the vitreous followed first order kinetics with a t1/2 of 62 hours; within 10 days after dosing only about 20% of unchanged fomivirsen remained in the vitreous. In the retina the estimated t1/2 was 79 hours. Similarly, in monkeys, fomivirsen clearance was complete within 14 days. The doses administered were roughly equivalent to the 165- and 330-mg doses studied in humans, with an estimated elimination half-life between 45 and 78 hours with the products of fomivirsen metabolism (multiple chain-shortened oligonucleotides) in both the vitreous and retina.

Mechanism of action

Fomivirsen is a member of the first generation of antisense oligonucleotides known as phosphorothioates. In this class of compounds, one of the oxygen atoms in the phosphate backbone is replaced by a sulfur atom. This modification results in a negatively charged molecule that is chiral at each phosphorothioate and serves to stabilize the molecule against DNase and RNase degradation, a significant improvement over the parent phosphodiester. Improvements in antisense chemistry over the past two decades have conveyed increased stability to the molecules, increasing in vivo half-lives and allowing for less frequent dosing. Modifying the paired C-G motifs by cytosine methylation reduces the proinflammatory effects that are typically seen with phosphorothioates.

Mechanism of action

Fomivirsen inhibits CMV by at least two mechanisms. The first is a sequence-specific antisense binding to inhibit expression of immediate-early genes, thus preventing viral replication. The second is sequence-independent and involves inhibition of adsorption of CMV to host cells, probably by direct binding to viral coat proteins. The reduction of immediate-early protein synthesis occurs in a dose-dependent manner. Although it does inhibit viral replication, fomivirsen does not eradicate the virus whose DNA, as for all herpesviruses, is integrated into the human genome. Therefore, treatment will have to continue for the life of the patient.

Pharmacokinetics

The series of clinical trials that led to approval by the U.S. Food and Drug Administration involved 430 eyes in 330 patients. Fomivirsen significantly delayed progression of CMV retinitis in patients with AIDS, including those who had failed treatment with ganciclovir or foscarnet, the first-line therapies. Fomivirsen is administered by intravitreal injection at doses of 165 μg once weekly for three weeks of induction and then once every two weeks. It also can be administered in a dose of 330 μg on days 1 and 15 and then once a month thereafter. Mean maximum retinal concentrations of fomivirsen occur at 2 days, and the elimination half-life after a single, 115-μg dose in monkey retina was 78 hours. There are no systemic side effects. Ocular side effects include increased intraocular pressure and mild to moderate intraocular inflammation that can be reversed with topical steroid treatment. It is important that side effects be minor, because treatment will be lifelong.

Clinical Use

Fomivirsen is used to treat CMV retinitis in patients with AIDS who have not responded to other treatments or in whom other treatments are contraindicated. It appears to be at least as effective as other treatments and produces fewer side effects. Because CMV retinitis is often associated with CMV infection elsewhere in the body, patients undergoing treatment with fomivirsen should be monitored for extraocular CMV disease.

Clinical Use

CMV retinitis in AIDS patients intolerant of, or unresponsive to, other treatments

Side effects

Iritis, which affects up to 25% of patients undergoing fomivirsen therapy, can be managed with topical corticosteroids. Vitreitis and increased intraocular pressure may also result from fomivirsen administration. Fomivirsen is contraindicated in patients who have been treated with cidofovir within the previous 2 to 4 weeks because cidofovir increases the risk of ocular inflammation.

Toxicity evaluation

The two most common adverse events reported were intraocular inflammation and an increase in intraocular pressure. Both the inflammatory reactions and the elevated intraocular pressure were transient and successfully treated with medication. Fomivirsen is contraindicated in patients with a known hypersensitivity to the drug. Fomivirsen is not recommended if the patient has been treated within the last 2–4 weeks with cidofovir (Vistides) as there may be an increased risk of inflammation in the eye. Animal reproductive studies have not been conducted with fomivirsen. No studies were conducted in pregnant women. Therefore, there are no data on whether fomivirsen would cause harm to the fetus when administered to a pregnant woman, nor is there any information on the potential effect on reproductive capacity or potential fetal toxicity.

Raw materials

Preparation Products