Macugen
pegaptanib
Sources:EMA assessment report ↗
Species
MonkeyRatMouseDogRabbit
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and dog (pivotal IVT); rat IV for systemic; supportive monkey, mouse
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
Why that species
VEGF highly conserved; identical binding sequence in rabbit and dog as in humans
“VEGF seems highly conserved between species and has an identical binding sequence in the pivotal toxicity species (rabbit and dog) as in humans.”
Surrogate molecule
No surrogate; clinical aptamer tested; nucleoside metabolites (2'-FU, 2'-FC) tested separately
“The two pegaptanib component modified nucleotides (2’-FU and 2’-FC) were evaluated in 90-day IV toxicity studies in woodchucks and rats.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Pivotal long term-studies in up to 9 months with intravitreous injections every 2 weeks did not cause any apparent toxic effects and there was no evidence of increased intra-ocular inflammation during the course of the studies.”
Pivotal GLP studies
6-month IVT rabbit and 9-month IVT dog (every 2 weeks, 6-week recovery); 13-week IV rat
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
Route in tox
Intravitreal (clinical route); IV and SC for systemic exposure
“The toxicology of pegaptanib was evaluated in mice, rats, rabbits, dogs and monkeys using the clinical route, IVT, and using SC and IV pegaptanib sodium administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted (GLP); pegaptanib and 2'-FU/2'-FC nucleosides negative overall
“Therefore, the carcinogenicity potential for pegaptanib sodium is considered low, based on the negative in vitro and in vivo genotoxicity assays for pegaptanib sodium and its component modified nucleotides.”
Carcinogenicity
Not conducted (very low systemic exposure; infeasible to model IVT plus systemic)
“The main argument considered by the CHMP in order to accept the lack of carcinogenicity studies was due to the very low systemic exposure obtained in the clinical population together with the apparent difficulty to perform relevant study obtaining both high systemic and intraocular exposure.”
Reproductive & developmental
Limited: mouse IV EFD (not teratogenic; developmental NOAEL 6.5 mg/kg); rabbit IVT range-finding only
“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”
Safety pharmacology
Stand-alone CV, respiratory, neurobehavioral studies at IV exposures up to 10x clinical; no effects
“Pegaptanib sodium was evaluated in animal models for cardiovascular, respiratory and neurobehavioral effects, at IV administered doses with associated systemic exposures up to 10-fold”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 3 mg/eye dog, 2 mg/eye rabbit; rat IV NOAEL 1 mg/kg/day (nephropathy, PEG vacuolated macrophages)
“In the peer-review, additional injection-related, but no drug-related findings were observed and a NOAEL of 3 mg/eye was confirmed.”
Risksopen answer page →
Immune & cytokine safety
No local/systemic immune response or antibody induction; antibody assay of unclear accuracy
“Overall, there were no indications that pegaptanib induced a local or systemic immune response and there were only minor effects on immune cells and organs at high exposures.”
Biodistribution & persistence
Retained in vitreous/retina; slow diffusion to systemic; kidney highest systemic; renal excretion
“After IVT administration, radioactivity was mainly located in the vitreous fluid, retina and aqueous humour at 24 hours post-dose.”
Modality-specific risk
2'-fluoro nucleoside metabolites (FIAU-like mitochondrial hepatotoxicity); PEG macrophage vacuolation; IVT injection/endotoxin effects
“As pegaptanib metabolism may result in systemic exposure to nucleosides structurally related to FIAU, a known hepatotoxicant (e.g., 2’-FU and 2’-FC).”