Lucentis
ranibizumab
Species
MonkeyRabbit
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (repeat-dose); rabbit for single-dose ocular studies
“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”
Why that species
Monkey and human VEGF very similar or identical; high activity on monkey VEGF expected, sufficient for intraocular use
“It is however agreed that it is likely that the monkey and human protein sequence are very similar, or even identical and a high activity on monkey VEGF is expected. For intraocular administration, this is considered sufficient.”
Surrogate molecule
No surrogate; the clinical antibody fragment was tested in cynomolgus monkeys
“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”
Species: general tox
Cynomolgus monkey (repeat-dose, up to 26 weeks); rabbit for single-dose ocular studies
“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”
Species: DART
Cynomolgus monkey (embryo-fetal development, intravitreal)
“An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.”
Species: carcinogenicity
Not conducted
“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”
Surrogate used in
No surrogate used; monkey and human VEGF likely very similar or identical
“It is however agreed that it is likely that the monkey and human protein sequence are very similar, or even identical and a high activity on monkey VEGF is expected.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”
Pivotal GLP studies
GLP monkey studies up to 26 weeks; bilateral 50 µl intravitreal injections every 2 weeks, up to 2.0 mg/eye
“Ranibizumab was administered bilaterally by 50 µl IVT injections every 2nd week at doses of up to 2.0 mg/eye.”
Route in tox
Intravitreal
“Ranibizumab was administered bilaterally by 50 µl IVT injections every 2nd week at doses of up to 2.0 mg/eye.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; acceptable given nature of compound
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
Carcinogenicity
Not conducted
“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”
Reproductive & developmental
Monkey EFD (intravitreal, organogenesis): low incidence of fetal skeletal abnormalities at 13x predicted human exposure
“Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure”
Safety pharmacology
No dedicated studies; endpoints incorporated into repeat-dose toxicity studies
“No safety pharmacology studies were performed. This was justified by the incorporation of safety pharmacology endpoints in repeat-dose toxicity studies”
Genotox: Ames
Not conducted (biologic)
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
Genotox: in vitro mammalian
Not conducted (biologic)
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
Genotox: in vivo
Not conducted (biologic)
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
Carcinogenicity model
Not conducted
“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”
Carcinogenicity timing
Not required; acceptable due to the nature of the compound
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
hERG / QT
Not conducted; safety pharmacology endpoints incorporated into repeat-dose studies, low systemic exposure
“No safety pharmacology studies were performed. This was justified by the incorporation of safety pharmacology endpoints in repeat-dose toxicity studies, and the human systemic exposure being below levels where any meaningful effect of a VEGF-related activity is expected.”
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 Lucentis 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts (EMA assessment report, p. 11)
NOAEL / key findings
No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts
“The NOEL or NOAEL were not identified in any of the studies, since all doses tested (0.25-2 mg) resulted in an ocular inflammation.”
Risksopen answer page →
Immune & cytokine safety
Highly immunogenic in rabbits; significant antigenicity in monkeys, even within the eye
“It is therefore not surprising that it is highly immunogenic in rabbits as shown in the single-dose ocular toxicity studies. A significant antigenicity was observed also in monkeys, even within the eye.”
Biodistribution & persistence
Serum levels >1000-fold below vitreous in rabbits and monkeys; aqueous humour and retina 2.5-4-fold below vitreous
“In rabbits and monkeys, serum levels were >1000-fold lower than vitreous concentrations. The levels in aqueous humour and retina were 2.5 – 4-fold lower than the vitreous levels.”
Modality-specific risk
Intraocular inflammation (immune-related to humanized protein) and theoretical neural retina, wound healing and embryo-fetal risks of VEGF blockade
“The majority of adverse effects of ranibizumab are considered related to the ocular inflammation.”
Anti-drug antibodies: animals
Highly immunogenic in rabbits; significant antigenicity in monkeys, even intraocular; most monkeys with perivascular sheathing were ADA-positive
“It is therefore not surprising that it is highly immunogenic in rabbits as shown in the single-dose ocular toxicity studies. A significant antigenicity was observed also in monkeys, even within the eye.”
Anti-drug antibodies: patients
Antibodies in approximately 1%-9% of patients after 6 to 24 months of monthly dosing; pre-treatment 0%-5%
“The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5% across treatment groups. After monthly dosing with LUCENTIS for 6 to 24 months, antibodies to LUCENTIS were detected in approximately 1%-9% of patients.”
Label warnings
- Endophthalmitis and Retinal Detachments
- Increases in Intraocular Pressure
- Thromboembolic Events
- Fatal Events in Patients with Diabetic Macular Edema and Diabetic Retinopathy at Baseline
- Retinal Vasculitis with or without Occlusion
Ocular toxicityThrombosis & embolismMetabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
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 Lucentis 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts (EMA assessment report, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey study (bilateral intravitreal); recovery phase length not stated
“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”
Pivotal GLP studies
GLP monkey studies up to 26 weeks; bilateral 50 µl intravitreal injections every 2 weeks, up to 2.0 mg/eye
“Ranibizumab was administered bilaterally by 50 µl IVT injections every 2nd week at doses of up to 2.0 mg/eye.”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development, intravitreal)
“An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.”
Reproductive & developmental
Monkey EFD (intravitreal, organogenesis): low incidence of fetal skeletal abnormalities at 13x predicted human exposure
“Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure”
PPND / ePPND: when
Not conducted: low systemic exposure and elderly AMD population
“No reproduction toxicology studies were performed. This was justified by the low systemic exposure of a compound for which the mechanism of action is well characterised during development, and the median age of the AMD-population (over 70 years).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”
Carcinogenicity model
Not conducted
“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”
Carcinogenicity timing
Not required; acceptable due to the nature of the compound
“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”
Safety marginopen answer page →
Safety margin at NOAEL
No ocular NOAEL; only the lowest dose (1.0-fold the clinical 0.5 mg dose, vitreous mg/ml) gave inflammation subsiding to vehicle levels
“In the vitreous, only the lowest dose tested (1.0-fold the clinical 0.5 mg dose on a mg/ml vitreous basis) in the 13-week study gave an inflammatory response that subsided to levels comparable to those observed in vehicle-injected animals while the animals were still on treatment.”
NOAEL / key findings
No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts
“The NOEL or NOAEL were not identified in any of the studies, since all doses tested (0.25-2 mg) resulted in an ocular inflammation.”
Efficacy evidenceopen answer page →
Efficacy evidence
Laser-induced choroidal neovascularisation (CNV) in monkeys; modified Miles vascular permeability assay
“The in vivo disease model used was the well established model of laser-induced CNV, in this case, in monkeys.”
Why that model
Monkey and human VEGF predicted to be near-identical, so ranibizumab is expected to be active in monkeys
“Identification of the sequence differences between monkey and humans (99% sequence homology, alignment predicting the protein products) resulted in a prediction of a 100% homology between the species on a protein level.”
Reviewer's view of the efficacy data
EMA: studies limited but sufficient as proof of principle; no adequate support for the clinical dosing regimen
“From a proof of principle point of view, the submitted studies, even though limited, are considered sufficient. However adequate support for the clinical dosing regimen has not been provided”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive toxicology studies
Why: Low systemic exposure, well-characterised mechanism, median AMD patient age over 70; segment II study needed for a younger population · Pharmacology or kinetics · Other reason
“No reproduction toxicology studies were performed. This was justified by the low systemic exposure of a compound for which the mechanism of action is well characterised during development, and the median age of the AMD-population (over 70 years).”
“The justifications are considered to be acceptable, but if ranibizumab should be intended in an indication in a younger population, a segment II study is needed.”
Safety pharmacologyAcceptedBeyond the letter
No formal safety pharmacology studies; endpoints incorporated into repeat-dose toxicity studies
Why: Endpoints in repeat-dose studies; human systemic exposure below levels with meaningful VEGF-related effect; no systemic toxicity at high exposure · Pharmacology or kinetics
“This was justified by the incorporation of safety pharmacology endpoints in repeat-dose toxicity studies, and the human systemic exposure being below levels where any meaningful effect of a VEGF-related activity is expected.”
“The absence of systemic toxicity at exposure levels highly above maximum clinical exposure (see Toxicology) is further reassuring and the lack of formal safety pharmacology studies is accepted.”
OtherAcceptedBeyond the letter
No standard systemic toxicology studies; single-dose ocular studies not to current guidelines and MTD not determined
Why: Knowledge of VEGF inhibition plus repeat-dose ocular studies; sufficient systemic safety margins · Pharmacology or kinetics · Weight of evidence
“The single dose studies were not according to present guidelines, and the maximum tolerated systemic dose was not determined. It is considered that with the present knowledge of the effects of VEGF-inhibition together with the information from repeat dose ocular toxicity studies, additional studies would not add to the safety evaluation of ranibizumab.”
“Consequently, from a systemic view-point there are sufficient margins of safety and therefore, the lack of standard systemic toxicology studies is acceptable.”
Safety marginCriticised but acceptedBeyond the letter
No ocular NOAEL: all doses tested (0.25-2 mg) caused ocular inflammation
Why: Ocular inflammation in the clinic appears non-serious and easily manageable · Human data
“The NOEL or NOAEL were not identified in any of the studies, since all doses tested (0.25-2 mg) resulted in an ocular inflammation.”
“Furthermore, in the clinic, the ocular inflammation appears to be non-serious and easily manageable.”
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