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.”
Species: general tox
Rabbit and dog (pivotal 6-month and 9-month intravitreal studies)
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
Species: DART
Mouse (definitive IV EFD) and rabbit (IVT range-finding EFD 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.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted.”
Surrogate used in
No surrogate used; VEGF binding sequence identical in rabbit, dog and human
“VEGF seems highly conserved between species and has an identical binding sequence in the pivotal toxicity species (rabbit and dog) as in humans.”
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”
Genotox: Ames
Negative for component nucleotides 2'-FU/2'-FC in Salmonella; small non-dose-related increase in a single E. coli strain
“In a battery of genotoxicity assays, 2’-FU and 2’-FC were negative in the Salmonella strains of the Ames assay, the SHE cell and the micronucleus assay but produced a small increase in revertant frequency with no relationship to dose in a single bacterial mutagenicity tester strain (E. coli).”
Genotox: in vitro mammalian
SHE cell assay negative (2'-FU and 2'-FC)
“In a battery of genotoxicity assays, 2’-FU and 2’-FC were negative in the Salmonella strains of the Ames assay, the SHE cell and the micronucleus assay but produced a small increase in revertant frequency with no relationship to dose in a single bacterial mutagenicity tester strain (E. coli).”
Genotox: in vivo
Micronucleus assay negative (2'-FU and 2'-FC)
“In a battery of genotoxicity assays, 2’-FU and 2’-FC were negative in the Salmonella strains of the Ames assay, the SHE cell and the micronucleus assay but produced a small increase in revertant frequency with no relationship to dose in a single bacterial mutagenicity tester strain (E. coli).”
Carcinogenicity model
Not conducted: very low systemic exposure and difficulty achieving both high systemic and intraocular exposure
“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.”
Carcinogenicity timing
Not required: CHMP accepted no carcinogenicity studies given very low systemic exposure
“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.”
hERG / QT
No hERG assay reported; no effects on cardiovascular, respiratory or neurobehavioral parameters at exposures above the 3 mg/eye clinical dose
“above the exposures observed after a 3 mg/eye clinical dose. All studies were claimed to be performed according to GLP. Pegaptanib did not affect these parameters”
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 Macugen 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: NOAEL 3 mg/eye dog, 2 mg/eye rabbit; rat IV NOAEL 1 mg/kg/day (nephropathy, PEG vacuolated macrophages) (EMA assessment report, p. 10)
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).”
Anti-drug antibodies: animals
No antibody induction observed; accuracy of the antibody assay unclear
“The compound did not induce lymphocyte proliferation and no induction of antibodies was observed, but the accuracy of the antibody assay is not clear.”
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.
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Macugen 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: NOAEL 3 mg/eye dog, 2 mg/eye rabbit; rat IV NOAEL 1 mg/kg/day (nephropathy, PEG vacuolated macrophages) (EMA assessment report, p. 10)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month beagle dog intravitreal study with 6-week recovery
“Dogs/Beagle 5-7/sex/group. Reversibility 2/sex in control and 3 mg groups. 0, 0.3, 1, 3 in 100µl/eye, IVT 9 months with 6 week recovery”
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.”
DART package
Species: DART
Mouse (definitive IV EFD) and rabbit (IVT range-finding EFD 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.”
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.”
PPND / ePPND: when
No PPND study: reproductive program limited to embryo-foetal development studies in mouse and rabbit
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted.”
Carcinogenicity model
Not conducted: very low systemic exposure and difficulty achieving both high systemic and intraocular exposure
“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.”
Carcinogenicity timing
Not required: CHMP accepted no carcinogenicity studies given very low systemic exposure
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat IV NOAEL plasma concentration ~240x human Cmax at 3 mg/eye
“The pegaptanib plasma concentration (30 minutes postdose on Day 91) at the NOAEL was approximately 240-fold higher than human maximum pegaptanib plasma concentrations following 3 mg/eye IVT doses.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse retinopathy of prematurity (hypoxia-induced retinal neovascularization), rat corneal pocket angiogenesis, guinea pig dermal permeability
“In vivo, administration of pegaptanib sodium inhibited hypoxia-induced retinal neovascularization in a murine model of retinopathy of prematurity, VEGF-induced corneal angiogenesis in a rat corneal pocket model, and dermal vascular leakage in a dermal vascular permeability (modified Miles) assay in guinea pigs.”
Why that model
In vivo testing feasible: pegaptanib also binds VEGF188, the murine ortholog of human VEGF189
“Pegaptanib also binds to VEGF188, the murine ortholog of human VEGF189, which is normally bound to the cell surface.”
Reviewer's view of the efficacy data
EMA: ROP mouse data have weaknesses but the submitted study is reasonable
“Even if the data obtained have their weaknesses, the submitted study is reasonable.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic intravitreal therapy
Why: Very low systemic exposure in patients; difficulty achieving both high systemic and intraocular exposure in a relevant study · Pharmacology or kinetics
“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.”
DARTVerdict not stated
No definitive non-rodent embryo-fetal study; only a non-GLP intravitreal rabbit dose-range-finding study
Why: Advanced age and limited reproductive potential of the AMD patient population · Other reason
“A full embryo-foetal toxicity in a non-rodent species (e.g., rabbits) was not conducted, but a non-GLP, rabbit dose-range-finding study with IVT administered pegaptanib was performed. This was justified with the advanced age and limited reproductive potential of the patient population with AMD.”
Impurity or metaboliteAcceptedBeyond the letter
Impurity intraocular safety margins only 2-3 fold
Why: Larger human eye than dog and rabbit increases the ratio to clinical local exposure · Pharmacology or kinetics
“With respect to intraocular toxicity, the safety margins are 2-3 fold. However, taking into account the larger human eye as compared to dogs and rabbits, the ratio to clinical local exposure is further increased and thus considered acceptable.”
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