Vitravene
fomivirsen
Sources:FDA review ↗
Species
MonkeyRabbit
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and monkey
“It appeared that intravitreal injection of ISIS 2922 caused cyclitis in the animals, monkeys and rabbits, and humans. The observed ocular changes were dose-dependent. In the severe cases, retina was involved in the ocular alterations.”
Why that species
No animal model of HCMV infection; antiviral activity shown only in vitro
“Due to lack of animal models for HCMV infection, the anti-CMV activity of fomivirsen has been demonstrated in in vitro tissue culture settings.”
Surrogate molecule
No surrogate; fomivirsen itself was injected intravitreally in rabbits and monkeys
“It appeared that intravitreal injection of ISIS 2922 caused cyclitis in the animals, monkeys and rabbits, and humans. The observed ocular changes were dose-dependent. In the severe cases, retina was involved in the ocular alterations.”
Species: general tox
Monkey and rabbit (intravitreal)
“It appeared that intravitreal injection of ISIS 2922 caused cyclitis in the animals, monkeys and rabbits, and humans.”
Species: DART
Not conducted: no reproductive toxicology information provided
“No information was provided.”
Species: carcinogenicity
Not conducted (waiver requested)
“A waiver from performing carcinogenicity studies was requested by the sponsor.”
Surrogate used in
No surrogate used; fomivirsen itself injected intravitreally in monkeys and rabbits
“It appeared that intravitreal injection of ISIS 2922 caused cyclitis in the animals, monkeys and rabbits, and humans.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“No intact fomivirsen was observed in any of tissues (kidney, liver, ovary, and uterus) following 1, 3, or 8 doses of 10 uM (115 ug) fomivirsen administered every-other-week for three months.”
Pivotal GLP studies
Cynomolgus monkey multiple-dose intravitreal ocular toxicity and systemic exposure study, with prophylactic corticosteroid
“To evaluate the effects of ISIS 2922 on ocular tissues in cynomolgus monkeys that have received prophylactic corticosteroid treatment and to determine the systemic exposure (i.e. plasma, kidney, liver, and uterus concentrations) following multiple intravitreal injection.”
Route in tox
Intravitreal
“Ocular kinetic parameters of fomivirsen following intravitreal injection to rabbits and monkeys are summarized in the following table.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: mutagenic potential evaluated in in vitro and in vivo assays
“The mutagenic potentials of fomivirsen were evaluated in both in vitro and in vivo systems and results were summarized in the following table.”
Carcinogenicity
Not conducted; waiver requested citing lack of meaningful systemic exposure
“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”
Reproductive & developmental
Not conducted; no reproductive toxicology information provided
“No information was provided.”
Safety pharmacology
ECG in repeat-dose intravitreal monkey study: no PR, QRS or QT changes, arrhythmia or conduction disturbances
“Neither significant changes in P-R, QRS, and Q-T intervals nor arrhythmia nor conduction disturbances were observed.”
Genotox: Ames
Not mutagenic (Salmonella)
“Ames Salmonella syphimurium: T498, TAI00, 6.7 - 5000 up/plate Not mutagenic”
Genotox: in vitro mammalian
Chromosome aberration in CHO-K1 cells: not clastogenic; mouse lymphoma assay result not legible
“Chromosome CHO-KI cells Aberration TReport N° ISIS 2922-1S01 : DETO 10, 800) , 800, or Not clastogenic”
Genotox: in vivo
Mouse bone marrow micronucleus assay conducted; result not stated legibly
“Micronucleus ICR mice -Bone Marrow Cells”
Carcinogenicity model
Not conducted: waiver citing lack of meaningful systemic exposure
“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”
Carcinogenicity timing
Not required: FDA accepted the carcinogenicity waiver
“the review division would accept the request from the sponsor for a waiver of carcinogenicity studies on fomivirsen.”
hERG / QT
No hERG assay; no PR, QRS or QT changes, arrhythmia or conduction disturbances on ECG in repeat-dose monkey study
“Neither significant changes in P-R, QRS, and Q-T intervals nor arrhythmia nor conduction disturbances were observed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Vitravene don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey 115 µg intravitreal with triamcinolone: no ocular alterations; transient IOP decrease in 3/6 (FDA review, p. 24)
NOAEL / key findings
Monkey 115 µg intravitreal with triamcinolone: no ocular alterations; transient IOP decrease in 3/6
“Group 2 (115 ug of fomivirsen + triamcinolone) or in control animals had no ocular alterations. A transient decrease in IOP was identified in 3/6 Group 2 animals.”
Risksopen answer page →
Immune & cytokine safety
Ocular inflammation in monkeys: acute anterior uveitis and cyclitis with inflammatory cells, flare and iris neovascularization
“Group 3 monkeys had acute anterior uveitis and cyclitis characterized by aqueous flare, inflammatory cells in the anterior chamber, hemorrhage into anterior chamber, and neovascularization of the iris, anterior synechiae of both irides as revealed by ophthalmic examination on Days 5, 8, 15 and 22.”
Biodistribution & persistence
Low systemic exposure after intravitreal dosing; in rabbits about 2 to 3% of dose in kidneys and liver
“Systemic exposure to fomivirsen following intravitreal administration was low. In rabbits treated with radiolabeled fomivirsen, it was possible to measure low levels (~2 to 3% of the total dose) of radioactivity in kidneys and liver.”
Modality-specific risk
Dose-dependent intraocular inflammation (cyclitis), with retinal involvement in severe cases
“It appeared that intravitreal injection of ISIS 2922 caused cyclitis in the animals, monkeys and rabbits, and humans. The observed ocular changes were dose-dependent. In the severe cases, retina was involved in the ocular alterations.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
NOAEL / key findings
Monkey 115 µg intravitreal with triamcinolone: no ocular alterations; transient IOP decrease in 3/6
“Group 2 (115 ug of fomivirsen + triamcinolone) or in control animals had no ocular alterations. A transient decrease in IOP was identified in 3/6 Group 2 animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro HCMV inhibition in primary human retinal pigment epithelial (RPE) cells
“In order to evaluate the ability of fomivirsen to inhibit CMV replication in retinal cells, primary human retinal pigment epithelial (RPE) cells were used as indicator cells.”
Why that model
No animal model of HCMV infection; activity shown only in tissue culture
“Due to lack of animal models for HCMV infection, the anti-CMV activity of fomivirsen has been demonstrated in in vitro tissue culture settings.”
Reviewer's view of the efficacy data
FDA: in vitro antiviral activity may reflect both sequence-dependent and sequence-independent effects
“Therefore, it is possible that the antiviral activity of fomivirsen observed is the results of a combination of sequence-dependent and sequence-independent effects via interfering specifically with viral replication processes.”
Similar precedents
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