Beyfortus
nirsevimab
Species
Monkey
Longest study
4 wk
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
Cynomolgus monkey only
“The non-clinical safety programme consisted of a 1-month repeat-dose toxicity study in cynomolgus monkeys and tissue cross-reactivity studies in human tissues”
Why that species
Exogenous viral target; monkey chosen for comparable human/cynomolgus FcRn affinity, as YTE substitution decreases exposure in rodents
“Therefore, use of cynomolgus monkeys as the relevant animal species for the non-clinical in vivo program of nirsevimab is endorsed based on the comparable affinity of nirsevimab to human and cynomolgus FcRn and the fact that the YTE substitution decreases antibody exposure in rodents.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (non-YTE parent antibody used only in cotton rat pharmacology)
“A repeat-dose toxicology study was conducted in cynomolgus monkeys to evaluate the potential toxicity of nirsevimab (study No 1468-038).”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“Dose and frequency of dosing Weekly for 4 weeks (5 injections total)”
Pivotal GLP studies
GLP 4-week cynomolgus monkey study, weekly IV (50 or 300 mg/kg) or IM (300 mg), 5 doses, with recovery period
“In the 4-week toxicity study with a 25-week recovery period once weekly i.v. or i.m. administration (5 doses total) of nirsevimab of 0, 300 mg/kg/week i.v. or 0 and 300 mg/kg/week i.m (6 monkeys/sex/group) or 50 mg/kg/week i.v.”
Route in tox
IV and IM
“Route of administration Either intravenous or intramuscular”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), genotoxicity studies are not required for biologics as they are not anticipated to interact with DNA or other genetic material.”
Carcinogenicity
Not conducted; weight-of-evidence assessment revealed no specific carcinogenic risk
“Carcinogenicity studies have not been conducted with nirsevimab. A weight of evidence approach was conducted in accordance with the FDA’s recommendations and applicable ICH guidelines for establishing the carcinogenic potential of nirsevimab and did not reveal any specific carcinogenic risk.”
Reproductive & developmental
Not conducted (ICH S6(R1)): exogenous viral target, infant population; no reproductive tissue effects or placental binding
“In accordance with ICH guideline S6(R1), no dedicated studies have been conducted to evaluate the effects of nirsevimab on fertility, embryo-foetal, and prenatal and postnatal development.”
Safety pharmacology
Incorporated into 4-week monkey study: no ECG, CNS or respiratory effects
“Safety pharmacology of nirsevimab was assessed as a component of the GLP 4-week repeat dose toxicology study in cynomolgus monkeys (Study #1468-038).”
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 Beyfortus 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: NOAEL 300 mg/kg IV or IM (highest dose); minor nonadverse APTT, globulin, total protein increases and splenic macrophage hypertrophy (FDA integrated review, p. 121)
NOAEL / key findings
NOAEL 300 mg/kg IV or IM (highest dose); minor nonadverse APTT, globulin, total protein increases and splenic macrophage hypertrophy
“No adverse, drug-related findings were observed in the GLP 4-week toxicology study in cynomolgus monkeys up to the highest doses tested (no observed adverse effect level (NOAEL) =300 mg/kg IM or IV).”
Risksopen answer page →
Immune & cytokine safety
No ADA during dosing; ADA in 4 (22.2%) recovery monkeys; no evidence of immunotoxicity
“None of the animals in the control or treated groups tested positive for ADA at any time point during the treatment phase. ADAs to nirsevimab was only observed in the recovery period and in a limited number of animals (four (22.2%) of the recovery animals).”
Biodistribution & persistence
No tissue cross-reactivity in human juvenile, neonatal and fetal tissue panels
“Results revealed no staining with nirsevimab, and therefore, no tissue cross-reactivity was identified against a panel of normal human juvenile, neonatal and foetal tissues.”
Modality-specific risk
Antibody-dependent enhancement of RSV disease; low risk on weight of evidence (no viral enhancement in cotton rats)
“the overall weight of evidence presented by the Applicant indicates a low risk of ADE of disease for nirsevimab.”
Similar precedents
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