Synagis
palivizumab
Species
no relevantMonkeyRat
Longest study
none
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
No repeat-dose studies; single-dose studies in rat and cynomolgus monkey only
“These results could be confirmed in Cynomolgus monkeys after a single administration of palivizumab.”
Why that species
Exogenous viral target; repeat-dose studies omitted owing to immunogenicity in animals and lack of human tissue binding
“The lack of repeated dose toxicity studies (including reproductive toxicity) was justified by the company by the immunogenicity of the human compound in animals and the lack of binding of the compound to a range of tissues.”
Surrogate molecule
No surrogate; the clinical antibody was tested in single-dose rat and cynomolgus monkey studies
“A single dose toxicity study of palivizumab administered to Sprague Dawley rats via intravenous injection including assessment of clinical signs, body weight changes, food consumption, ophthalmoscopy, haematology, clinical and anatomic pathology until 14 days post injection”
Species: general tox
None: no repeat-dose toxicity studies (justified by immunogenicity in animals and lack of tissue binding)
“The lack of repeated dose toxicity studies (including reproductive toxicity) was justified by the company by the immunogenicity of the human compound in animals and the lack of binding of the compound to a range of tissues.”
Species: DART
Not conducted (product indicated only for infants)
“The applicant stated in the preclinical expert report that since the product is indicated only for use in infants there is no need to evaluate the potential toxicity of palivizumab on the reproduction.”
Species: carcinogenicity
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Surrogate used in
No surrogate used; palivizumab itself tested in rat and cynomolgus monkey
“These results could be confirmed in Cynomolgus monkeys after a single administration of palivizumab.”
Study lengthopen answer page →
Longest pivotal study
0 (no repeat-dose studies; single-dose only)
“Studies on repeated dose toxicity, effects on the reproduction, embryo-foetal & perinatal toxicity, mutagenic potential, oncogenic/carcinogenic potential and ecotoxicity/environmental risk assessment were not considered necessary by the applicant and were not performed.”
Pivotal GLP studies
No repeat-dose studies; single IV dose in Sprague Dawley rats (14-day observation) and cynomolgus monkeys; no toxicity
“A single dose toxicity study of palivizumab administered to Sprague Dawley rats via intravenous injection including assessment of clinical signs, body weight changes, food consumption, ophthalmoscopy, haematology, clinical and anatomic pathology until 14 days post injection gave no indication of toxicity”
Route in tox
Intravenous (single-dose studies); local tolerance in rabbits
“A single dose toxicity study of palivizumab administered to Sprague Dawley rats via intravenous injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Carcinogenicity
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Reproductive & developmental
Not conducted; product not indicated for adults or females of reproductive potential
“Pregnancy Category C: Synagis® 110 is not indicated for adult usage and animal reproduction studies have not been conducted.”
Safety pharmacology
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.
Genotox: Ames
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Genotox: in vitro mammalian
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Genotox: in vivo
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Carcinogenicity model
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Carcinogenicity timing
Not considered necessary; not performed
“Studies on repeated dose toxicity, effects on the reproduction, embryo-foetal & perinatal toxicity, mutagenic potential, oncogenic/carcinogenic potential and ecotoxicity/environmental risk assessment were not considered necessary by the applicant and were not performed.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Synagis 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 toxicity after single IV doses in rats and monkeys; no injection-site effects in rabbit local tolerance study (EMA assessment report, p. 5)
NOAEL / key findings
No toxicity after single IV doses in rats and monkeys; no injection-site effects in rabbit local tolerance study
“gave no indication of toxicity or statistically significant deviations from normal caused by the test article for the described parameters.”
Risksopen answer page →
Immune & cytokine safety
Immunogenic in cynomolgus monkeys: anti-drug antibodies in low- and high-dose groups
“Palivizumab was immunogenic in Cynomolgus monkeys and led to the generation of anti”
Biodistribution & persistence
No binding in tissue cross-reactivity study with pediatric human tissues
“No binding was observed in any of the tested human tissues.”
Modality-specific risk
Low target-related risk (viral antigen, no human tissue binding); hypersensitivity and anaphylaxis
“No binding was observed in any of the tested human tissues.”
Anti-drug antibodies: animals
Anti-palivizumab antibodies in 1/4 monkeys in both low- and high-dose groups
“Palivizumab was immunogenic in Cynomolgus monkeys and led to the generation of anti-palivizumab antibodies in the low dosage- as well as in the high dosage group in 1/4 animals.”
Anti-drug antibodies: patients
0.7% with Synagis vs 1.1% placebo after the fourth injection (Trial 1)
“In Trial 1, the incidence of anti-palivizumab antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the Synagis group.”
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 Synagis 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 toxicity after single IV doses in rats and monkeys; no injection-site effects in rabbit local tolerance study (EMA assessment report, p. 5)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single-dose studies only; not considered necessary)
“Studies on repeated dose toxicity, effects on the reproduction, embryo-foetal & perinatal toxicity, mutagenic potential, oncogenic/carcinogenic potential and ecotoxicity/environmental risk assessment were not considered necessary by the applicant and were not performed.”
Pivotal GLP studies
No repeat-dose studies; single IV dose in Sprague Dawley rats (14-day observation) and cynomolgus monkeys; no toxicity
“A single dose toxicity study of palivizumab administered to Sprague Dawley rats via intravenous injection including assessment of clinical signs, body weight changes, food consumption, ophthalmoscopy, haematology, clinical and anatomic pathology until 14 days post injection gave no indication of toxicity”
DART package
Species: DART
Not conducted (product indicated only for infants)
“The applicant stated in the preclinical expert report that since the product is indicated only for use in infants there is no need to evaluate the potential toxicity of palivizumab on the reproduction.”
Reproductive & developmental
Not conducted; product not indicated for adults or females of reproductive potential
“Pregnancy Category C: Synagis® 110 is not indicated for adult usage and animal reproduction studies have not been conducted.”
PPND / ePPND: when
Not conducted; reproductive toxicity not evaluated because the product is indicated only for infants
“The applicant stated in the preclinical expert report that since the product is indicated only for use in infants there is no need to evaluate the potential toxicity of palivizumab on the reproduction.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Carcinogenicity model
Not conducted
“Carcinogenesis, mutagenesis, and reproductive toxicity studies have not been performed.”
Carcinogenicity timing
Not considered necessary; not performed
“Studies on repeated dose toxicity, effects on the reproduction, embryo-foetal & perinatal toxicity, mutagenic potential, oncogenic/carcinogenic potential and ecotoxicity/environmental risk assessment were not considered necessary by the applicant and were not performed.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
No toxicity after single IV doses in rats and monkeys; no injection-site effects in rabbit local tolerance study
“gave no indication of toxicity or statistically significant deviations from normal caused by the test article for the described parameters.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cotton rat RSV infection model: lung virus titres reduced prophylactically and therapeutically at 5 mg/kg IM or IV
“Palivizumab was able to reduce the virus titres in the lungs when applied prophylactically or as a treatment for an ongoing infection from approx. 105 to 102 Pfu/gram lung at concentrations of 5 mg/kg after either IM or IV administration.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: >99% titre reduction for RSV A and B strains at 5 mg/kg and prevention of lung histopathology indicate efficacy
“At the concentration of 5mg/kg the virus titres of group A as well as group B strains of RSV were >99% reduced. Prevention of the formation of histopathological changes in the lung was a further parameter studied, indicating the efficacy of palivizumab.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No repeat-dose toxicity studies (including reproductive toxicity); single-dose studies only
Why: Immunogenicity of the humanised antibody in animals; no tissue binding; clinical studies showed no repeat-dosing toxicity problems · Pharmacology or kinetics · Human data
“The lack of repeated dose toxicity studies (including reproductive toxicity) was justified by the company by the immunogenicity of the human compound in animals and the lack of binding of the compound to a range of tissues.”
“However, the ensuing clinical studies have not revealed significant toxicity problems related to repeated dosing.”
DARTVerdict not stated
No reproductive toxicity evaluation
Why: Indicated only for infants · Other reason
“The applicant stated in the preclinical expert report that since the product is indicated only for use in infants there is no need to evaluate the potential toxicity of palivizumab on the reproduction.”
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