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.”
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”
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 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: 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.”