Fomivirsen

Identification

Name
Fomivirsen
Accession Number
DB06759
Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Description

Fomivirsen is a antisense 21 mer phosphorothioate oligonucleotide. It is an antiviral agent that was used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. As a complementary nucleotide to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, it disrupts the replication of the virus through an antisense mechanism [6]. It was discovered at the NIH and was licensed and initially developed by Isis Pharmaceuticals, which subsequently licensed it to Novartis [3]. The drug was withdrawn by the FDA because while there was a high unmet need for drugs to treat CMV when the drug was initially discovered and developed due to the CMV arising in people with AIDS, the development of HAART dramatically reduced the number of cases of CMV. Fomivirsen is marketed under the trade name Vitravene for intravitreal injection and was the first antisense drug to be approved by the Food and Drug Administration (FDA).

Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Fomivirsen sodium3Z6W3S36X5160369-77-7Not applicable
Categories
UNII
QX5LK7YCHV
CAS number
144245-52-3

Pharmacology

Indication

Indicated for the local treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), when other therapy has been ineffective or is considered unsuitable [Label].

Pharmacodynamics

Fomivirsen is an antiviral agent that inhibits CMV replication in a dose-dependent manner with a mean 50% inhibitory concentration between 0.03 and 0.2 μM in a number of in vitro cell lines [2]. In human fibroblast cell lines, the median effective inhibitory concentration (EC50) of fomivirsen for virus antigen production was approximately 0.34±0.25 μM [6]. In a clinical trial, administration of fomivirsen in patients with newly diagnosed CMV retinitis resulted in an increased median time to disease progression in the immediate treatment group versus delayed treatment group [6].

Mechanism of action

Fomivirsen is a phosphorothioate oligonucleotide that inhibits the replication of human cytomegalovirus (HCMV) through an antisense mechanism. The nucleotide sequence is complementary to a sequence in mRNA transcripts of the major immediate early region 2 (IE2) of human CMV, which encodes several proteins responsible for regulation of viral gene expression that are essential for viral replication [6]. The IE2 gene is essential for early viral gene expression and viral replication [4]; it was shown that the IE2 gene transactivate most human CMV promoters [5]. Protein product from the IE2 region also acts as autorepressor that represses transcription of the IE1 and IE2 genes by binding the cis repression sequence (CRS) [4]. It is proposed that the IE2 region interacts with multiple basal and general transcription factors, as well as cell cycle regulators, and it also plays a critical role in controlling the entry of the virus into the lytic cycle from the latent state to further potentiate the infection cascade [5]. Upon binding to the target mRNA, fomivirsen inhibits the IE2 protein synthesis and disrupts viral replication [6].

TargetActionsOrganism
A30 kDa immediate-early protein 2
antisense oligonucleotide
Human cytomegalovirus (strain Towne)
A45 kDa immediate-early protein 2
antisense oligonucleotide
Human cytomegalovirus (strain Towne)
Absorption

Following intravitreal injection in rabbits and monkeys, peak concentrations in the vitreous was detectable immediately after injection with the concentrations increasing in a dose-proportional manner [6]. Due to low doses of intravitreal administration with slow disposition from the eye, there is limited absorption of the drug into the systemic circulation [1]. Fomivirsen is detectable in retina of rabbits within hours following administration and concentrations increase over 3 to 5 days. The concentrations of the drug were highest in the retina and iris [Label].

Volume of distribution

Preclinical studies show that fomivirsen distributes to retina [1].

Protein binding

Fomivirsen is approximately 40% bound to proteins according to the analysis of vitreous samples from treated rabbits and monkeys [Label]. It is mostly bound to albumin and alpha2-macroglobulin in blood plasma [1].

Metabolism

Fomivirsen undergoes metabolism mediated by endo- and exonuclease, where the resides from the terminal ends of the oligonucleotide are sequentially removed [Label]. Resulting shortened oligonucleotides and mononucleotide metabolites can be detected in the retina and vitreous of animals [Label]. Mononucleotides may also be further catabolized to endogenous nucleotides and excreted as low molecular weight metabolites [Label].

Route of elimination

In rabbits, 16% of total radiolabelled fomivirsen was detected in urine and 3% was detected in feces [Label].

Half life

Intravitreal drug clearance studies have revealed first-order kinetics [2]. Following intravitreal administration, fomivirsen is slowly cleared from vitreous with a half-life of approximately 55 hours in humans [1]. The half life from retina in monkeys following administration of 115 mcg fomivirsen is estimated to be 78 hours [1].

Clearance

Clearance from retina was shown to be similarly slow following loading from the vitreous [1].

Toxicity

There has been one case of accidental overdose of fomivirsen with administration once bilaterally with 990 μg per eye; vision was restored with anterior chamber paracentesis performed bilaterally [6]. According to the findings in Salmonella/Microsome (Ames) and mouse lymphoma tests, fomivirsen was not shown to be mutagenic. In the in vivo mouse micronucleus assay, fomivirsen was not clastogenic. Animal reproductive studies or studies evaluating the carcinogenic potential of fomivirsen has not been conducted [Label].

Affected organisms
  • Human Cytomegalovirus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
Varicella Zoster Vaccine (Live/Attenuated)The therapeutic efficacy of Varicella Zoster Vaccine (Live/Attenuated) can be decreased when used in combination with Fomivirsen.
Food Interactions
Not Available

References

General References
  1. Geary RS, Henry SP, Grillone LR: Fomivirsen: clinical pharmacology and potential drug interactions. Clin Pharmacokinet. 2002;41(4):255-60. doi: 10.2165/00003088-200241040-00002. [PubMed:11978144]
  2. de Smet MD, Meenken CJ, van den Horn GJ: Fomivirsen - a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul Immunol Inflamm. 1999 Dec;7(3-4):189-98. [PubMed:10611727]
  3. Orr RM: Technology evaluation: fomivirsen, Isis Pharmaceuticals Inc/CIBA vision. Curr Opin Mol Ther. 2001 Jun;3(3):288-94. [PubMed:11497353]
  4. Isomura H, Stinski MF: The human cytomegalovirus major immediate-early enhancer determines the efficiency of immediate-early gene transcription and viral replication in permissive cells at low multiplicity of infection. J Virol. 2003 Mar;77(6):3602-14. [PubMed:12610136]
  5. Marchini A, Liu H, Zhu H: Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes. J Virol. 2001 Feb;75(4):1870-8. doi: 10.1128/JVI.75.4.1870-1878.2001. [PubMed:11160686]
  6. EMA Label: Vitravene (fomivirsen sodium) Summary of Product Characteristics [Link]
External Links
KEGG Drug
D02736
PubChem Substance
347910367
ChEMBL
CHEMBL1201688
Wikipedia
Fomivirsen
ATC Codes
S01AD08 — Fomivirsen
FDA label
Download (291 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCytomegalovirus Retinitis / Human Immunodeficiency Virus (HIV) Infections2
Not AvailableCompletedTreatmentCytomegalovirus Retinitis / Human Immunodeficiency Virus (HIV) Infections2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human cytomegalovirus (strain Towne)
Pharmacological action
Yes
Actions
Antisense oligonucleotide
General Function
Activates the E1.7 promoter. This activation is augmented by the IE1 protein. It down-regulates the transcription of genes under the control of the major IE promoter.
Specific Function
Not Available
Gene Name
UL122
Uniprot ID
P06434
Uniprot Name
30 kDa immediate-early protein 2
Molecular Weight
30328.565 Da
References
  1. Mulamba GB, Hu A, Azad RF, Anderson KP, Coen DM: Human cytomegalovirus mutant with sequence-dependent resistance to the phosphorothioate oligonucleotide fomivirsen (ISIS 2922). Antimicrob Agents Chemother. 1998 Apr;42(4):971-3. [PubMed:9559825]
Kind
Protein
Organism
Human cytomegalovirus (strain Towne)
Pharmacological action
Yes
Actions
Antisense oligonucleotide
General Function
Activates the E1.7 promoter. This activation is augmented by the IE1 protein. It down-regulates the transcription of genes under the control of the major IE promoter.
Specific Function
Dna binding
Gene Name
UL122
Uniprot ID
P06435
Uniprot Name
45 kDa immediate-early protein 2
Molecular Weight
44773.175 Da
References
  1. Mulamba GB, Hu A, Azad RF, Anderson KP, Coen DM: Human cytomegalovirus mutant with sequence-dependent resistance to the phosphorothioate oligonucleotide fomivirsen (ISIS 2922). Antimicrob Agents Chemother. 1998 Apr;42(4):971-3. [PubMed:9559825]

Drug created on September 14, 2010 10:21 / Updated on November 02, 2018 08:52