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.”
Species: general tox
Cynomolgus monkey (IV, 4-, 13- and 26-week studies)
“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.”
Species: DART
Rabbit (embryo-fetal development)
“Studies on embryofoetal development were performed in rabbit.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were performed.”
Surrogate used in
Yes (pharmacology only): parent murine antibody A4.6.1 in xenograft models
“The pharmacology of an anti-VEGF approach was investigated primarily in murine xenograft models using the parent murine antibody A4.6.1.”
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”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were performed.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were performed.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were performed.”
Carcinogenicity model
Not conducted
“No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.”
Carcinogenicity timing
Not required: omission accepted for this type of compound
“The omission of genotoxicity and carcinogenicity studies is acceptable for this type of compound [107].”
hERG / QT
No hERG assay; no ECG, blood pressure or respiration effects in monkeys at 2-50 mg/kg IV for up to 26 weeks
“No treatment-related effects on physical examinations, including respiration rate, blood pressure, ECG, rectal body temperature and urinalysis, were observed in cynomolgus monkeys administered 2 to 50 mg/kg of bevacizumab IV once or twice weekly for up to 26 weeks.”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
Monkey 26-week: very weak anti-Fab antibodies in one 50 mg/kg animal (and one control, assay interference)
“Serum from one control animal at study day 15 and serum from one 50 mg/kg animal at day 183 were positive for antibodies to bevacizumab. The responses were very weak (just above the minimal detectable level) and were directed to the Fab portion of bevacizumab.”
Anti-drug antibodies: patients
0.6% (14/2233) treatment-emergent ADA in adjuvant solid tumour studies; 3 of 14 neutralizing
“In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA).”
Label warnings
- Gastrointestinal Perforations and Fistulae
- Surgery and Wound Healing Complications
- Hemorrhage
- Arterial Thromboembolic Events
- Venous Thromboembolic Events
- Hypertension
- Posterior Reversible Encephalopathy Syndrome
- Renal Injury and Proteinuria
- Infusion-Related Reactions
- Embryo-Fetal Toxicity
- Ovarian Failure
- Congestive Heart Failure (CHF)
GastrointestinalBleedingThrombosis & embolismCardiovascularNeurotoxicityNephrotoxicityHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV) with 12-week recovery
“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.”
DART package
Species: DART
Rabbit (embryo-fetal development)
“Studies on embryofoetal development were performed in rabbit.”
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.”
PPND / ePPND: when
PPND not conducted: omission accepted because key reproductive endpoints were covered by the rabbit embryo-fetal (segment II) study
“The omission of prenatal and postnatal development, including maternal function studies can be accepted, because the most important parts of reproductive toxicology were examined in the segment II study.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were performed.”
Carcinogenicity model
Not conducted
“No studies have been conducted to assess potential of bevacizumab for carcinogenicity or mutagenicity.”
Carcinogenicity timing
Not required: omission accepted for this type of compound
“The omission of genotoxicity and carcinogenicity studies is acceptable for this type of compound [107].”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey physeal dysplasia at exposures ~1.5- to 2.0-fold below expected human exposure (average serum concentration)
“Based on weekly dose, this effect occurred at dose levels slightly below (>0.8-fold) the proposed clinical dose, and exposure levels were approximately 1.5- to 2.0-fold below the expected human clinical exposure, based on average serum concentrations.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumour xenografts in nude mice, mainly with murine parent A4.6.1; bevacizumab also inhibited breast, prostate and ovarian xenografts
“Mono-therapy with A4.6.1, bevacizumab, paclitaxel [76, 79], or doxorubicin [88] inhibited tumour growth and angiogenesis in tumours from human breast cancer [88], prostate cancer [79] and ovarian cancer [76].”
Why that model
Bevacizumab does not bind endogenous mouse or rat VEGF; binds monkey VEGF and rabbit VEGF (lower affinity)
“The pharmacokinetics of bevacizumab was investigated in species where the antibody is expected to bind to and neutralise endogenous VEGF, i.e., cynomolgus monkeys [41] and rabbits (albeit with lower affinity than for human VEGF, see toxicology), and in mice and rats, where it is reported not to bind endogenous VEGF [42].”
Reviewer's view of the efficacy data
EMA: pharmacology mostly with A4.6.1, but equivalence to bevacizumab adequately documented (VEGF affinity, anti-proliferative effect)
“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.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No pre- and postnatal development study; rabbit embryo-fetal study only
Why: Most important parts of reproductive toxicology examined in the segment II study · Weight of evidence
“The omission of prenatal and postnatal development, including maternal function studies can be accepted, because the most important parts of reproductive toxicology were examined in the segment II study.”
Safety marginVerdict not stated
Physeal dysplasia in monkeys at exposures about 1.5- to 2.0-fold below expected human exposure
“Based on weekly dose, this effect occurred at dose levels slightly below (>0.8-fold) the proposed clinical dose, and exposure levels were approximately 1.5- to 2.0-fold below the expected human clinical exposure, based on average serum concentrations.”
Efficacy modelAcceptedBeyond the letter
Most pharmacology studies used the murine parent antibody A4.6.1 rather than bevacizumab
Why: Equivalence to bevacizumab documented for VEGF affinity and anti-proliferative effect · Pharmacology or kinetics
“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.”
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