Avastin
bevacizumab
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 and rabbit
“Toxicology studies were performed in cynomolgus monkeys and rabbits.”
Why that species
Cyno VEGF predicted identical to human; binds rabbit VEGF with lower affinity (Kd 8.0 vs 1.1 nM)
“Cynomolgus monkey VEGF is predicted to have a protein sequence identical to that of human VEGF [41]. According to the applicant, bevacizumab also binds rabbit VEGF, although with a lower affinity than for human VEGF; the dissociation constant (Kd) is 8.0 nM for rabbit VEGF compared with 1.1 nM for human VEGF.”
Surrogate molecule
No surrogate in toxicology; murine parent A4.6.1 used for pharmacology; clinical antibody tested in monkey and rabbit
“Most submitted pharmacological studies are performed with A4.6.1 but equivalence between bevacizumab and A4.6.1 has been adequately documented with regard to VEGF affinity and anti-proliferative effect.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Additionally, a 26-week iv with a 12-week recovery was conducted in adult cynomolgus monkeys.”
Pivotal GLP studies
Cynomolgus monkey IV 4- and 13-week (twice weekly) and 26-week studies with 12-week recovery
“Twice weekly iv administration of rhuMAbVEGF for 4 or 13 weeks were carried out in young adult to adult cynomolgus monkeys [91]. Additionally, a 26-week iv with a 12-week recovery was conducted in adult cynomolgus monkeys.”
Route in tox
Intravenous
“The toxicology program was designed to support IV administration of bevacizumab.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genotoxicity studies were performed.”
Carcinogenicity
Not conducted
“No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.”
Reproductive & developmental
Rabbit EFD: maternal NOAEL 10 mg/kg, fetal NOAEL <10 mg/kg; reduced fetal weight and ossification, malformations
“The maternal NOAEL was 10 mg/kg. The foetal NOAEL was less than 10 mg/kg, since all treatment doses reduced foetal weights and number of ossification sites, whereas the two higher treatment doses produced a statistically significant increase in multiple malformations.”
Safety pharmacology
No dedicated studies; assessed in monkey toxicology studies with no effects on respiration, blood pressure, ECG or temperature
“Safety pharmacology endpoints were evaluated as part of the toxicology studies (see Toxicology). No treatment-related effects on physical examinations, including respiration rate, blood pressure, ECG, rectal body temperature and urinalysis, were observed”
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 Avastin 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 oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: No NOAEL stated; physeal dysplasia from about 2 mg/kg (males) and 10 mg/kg (females) in monkeys (EMA assessment report, p. 21)
NOAEL / key findings
No NOAEL stated; physeal dysplasia from about 2 mg/kg (males) and 10 mg/kg (females) in monkeys
“Physeal dysplasia occurred in males at about 2 mg/kg and in females at 10 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
Rabbits developed anti-drug antibodies 8-11 days after start of dosing, limiting rabbit study duration
“Antibodies developed between 8 and 11 days after the initiation of dosing.”
Biodistribution & persistence
Crossed the rabbit placenta; fetal serum concentrations mostly exceeded maternal (median ratio 1.87)
“In most cases, foetal serum concentrations were greater than maternal serum concentrations with a median ratio of foetal serum:maternal serum concentrations of 1.87.”
Modality-specific risk
VEGF inhibition: dose-dependent physeal dysplasia from blocked vessel formation in growth plates
“The toxicity included a dose-dependent occurrence of physeal dysplasia secondary to the inhibition of blood vessel formation in long bone growth plates.”