Adstiladrin
nadofaragene firadenovec
Species
MonkeyRat
Longest study
22 wk (derived)
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey for rAd-IFN/Syn3 GLP tox; rat and monkey for excipient Syn3
“Rat and cynomolgus monkey have been used as the toxicology species for Syn3NODA and cynomolgus monkeys were used for the toxicological assessment of rAd-IFN/Syn3NODA.”
Why that species
Monkey shows systemic vector exposure after intravesical dosing (unlike rodents), a worst-case model; permissiveness not otherwise discussed
“As a toxicological species, monkeys may be a worst-case model, since systemic toxicity of rAd-IFN will be of very limited relevance to the clinical situation.”
Surrogate molecule
No surrogate; clinical rAd-IFN/Syn3 tested intravesically in monkeys (human IFN-alpha2b transgene)
“Safety was assessed in cynomolgus monkeys receiving intravesical administration of rAd”
Study lengthopen answer page →
Longest pivotal study
22 (derived from the dosing and observation schedule)
“dose levels of 2.5 x 1011 vp/animal (1x1011 vg rAd-IFN/mL in 1 mg/mL Syn3), 1.25 x 1013 vp/animal (5x1011 vg rAd-IFN/mL in 1 mg/mL Syn3), Syn3 alone (1mg/mL), or placebo control on Days 1 and 91, followed by a two month observation period”
Pivotal GLP studies
GLP monkey intravesical study: 2 doses (Days 1 and 91) of rAd-IFN/Syn3 at 2.5e11 or 1.25e13 vp/animal, Syn3 alone, placebo; 2-month observation
“on Days 1 and 91, followed by a two month observation period in a GLP toxicology study.”
Route in tox
Intravesical (clinical route); IV for Syn3 excipient
“studies involving the intravesical (the intended clinical route of administration) and intravenous (IV) routes of administration in rats and cynomolgus monkeys have been conducted.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
“Safety pharmacology, pharmacokinetics, toxicology, and genotoxicity studies were also conducted for the exicipient Syn3.”
Carcinogenicity
Not conducted (not warranted by product characteristics, tox results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”
Reproductive & developmental
Not conducted (not warranted by product characteristics, tox results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”
Safety pharmacology
No dedicated vector study; excipient Syn3 in vitro hERG and in vivo CNS/CV/respiratory studies showed no risk up to 5 mg/kg
“Safety pharmacology studies do not indicate a risk for Syn3NODA in the in vivo studies evaluating CNS, cardiovascular and respiratory systems up to a concentration of 5 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Local NOAEL not set (urinary tract changes at all doses, reversible); highest non-severely toxic dose 1.25e13 vp rAd-IFN with 25 mg Syn3; bladder/ureter/urethra inflammation
“25 mg Syn3NODA and 1.25x1013 vp rAd-IFN could be considered the highest non-severely toxic dose.”
Risksopen answer page →
Immune & cytokine safety
Neutralizing anti-adenovirus and anti-IFNa2b antibodies in most high-dose monkeys, persisting through observation period
“Development of neutralizing antibodies to the adenovirus and anti-IFNα2b antibodies occurred in the majority of animals in the high dose group and to a lesser extent in the low dose group”
Biodistribution & persistence
Vector DNA in bladder (Days 8, 98); blood within 24 h; urine 2-3 days; low levels in liver, kidney, gonads; none in reproductive tissue at end
“Biodistribution analysis indicated the presence of rAd-IFN DNA in the bladder on Days 8 and 98.”
Modality-specific risk
Local urothelial toxicity of intravesical vector/Syn3 (inflammation, ulceration, fibrosis); anti-vector immunity; limited systemic spread
“Findings in the urinary bladder included mononuclear cell infiltration, inflammation, cytoplasmic vacuolation, urothelial hyperplasia, ulceration, and chronic inflammation”