Explore a selection of our essential drug information below, or:
Identification
- Generic Name
- Fomivirsen
- DrugBank Accession Number
- DB06759
- Background
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 by scientists at the National Institutes of Health (NIH) and was first developed by Isis Pharmaceuticals and subsequently licensed 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 The drug was withdrawn by the FDA because while there was a high unmet need for drugs to treat CMV when the drug was initially discovered and developed due to the CMV arising in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).
- Type
- Biotech
- Groups
- Approved, Investigational, Withdrawn
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- Fomivirsen
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,6.
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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.
Target Actions Organism A30 kDa immediate-early protein 2 antisense oligonucleotideHuman cytomegalovirus (strain Towne) A45 kDa immediate-early protein 2 antisense oligonucleotideHuman 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,6. 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.
- Adverse Effects
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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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Products
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Ingredient UNII CAS InChI Key Fomivirsen sodium 3Z6W3S36X5 160369-77-7 Not applicable
Categories
- ATC Codes
- S01AD08 — Fomivirsen
- Drug Categories
- Anti-Infective Agents
- Antisense Elements (Genetics)
- Antisense Oligonucleotides
- Antiviral Agents
- Compounds used in a research, industrial, or household setting
- Laboratory Chemicals
- Molecular Probes
- Nucleic Acid Probes
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- Nucleotides
- Oligonucleotides
- Ophthalmologicals
- Polynucleotides
- Sensory Organs
- Sulfur Compounds
- Classification
- Not classified
- Affected organisms
- Human Cytomegalovirus
Chemical Identifiers
- UNII
- QX5LK7YCHV
- CAS number
- 144245-52-3
References
- General References
- 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. [Article]
- 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. [Article]
- Orr RM: Technology evaluation: fomivirsen, Isis Pharmaceuticals Inc/CIBA vision. Curr Opin Mol Ther. 2001 Jun;3(3):288-94. [Article]
- 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. [Article]
- 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. [Article]
- EMA Label: Vitravene (fomivirsen sodium) Summary of Product Characteristics [Link]
- External Links
- KEGG Drug
- D02736
- PubChem Substance
- 347910367
- 85763
- ChEMBL
- CHEMBL1201688
- Wikipedia
- Fomivirsen
- FDA label
- Download (291 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Cytomegalovirus Retinitis / Human Immunodeficiency Virus (HIV) Infections 2 somestatus stop reason just information to hide Not Available Completed Treatment Cytomegalovirus Retinitis / Human Immunodeficiency Virus (HIV) Infections 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intraocular - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
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
- 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. [Article]
- 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
- 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. [Article]
Drug created at September 14, 2010 16:21 / Updated at June 02, 2024 21:58