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).”
Species: general tox
Cynomolgus monkey (1-month repeat-dose study)
“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”
Species: DART
Not conducted (ICH S6(R1)): exogenous viral target
“Dedicated in vivo DART studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”
Species: carcinogenicity
Not conducted
“Carcinogenesis, mutagenesis and reproductive toxicity studies have not been performed with BEYFORTUS.”
Surrogate used in
Yes (pharmacology only): parental non-YTE antibody 1G7 used in rodent studies
“Therefore, the parental molecule, 1G7, was utilized for nonclinical pharmacology studies conducted in rodents.”
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).”
Genotox: Ames
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.”
Genotox: in vitro mammalian
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.”
Genotox: in vivo
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 model
Not conducted; weight-of-evidence assessment found 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.”
Carcinogenicity timing
Not required: non-endogenous viral target, intermittent use (ICH S6(R1))
“Thus, in accordance with ICH guideline S6(R1) the omission of carcinogenicity studies is considered acceptable.”
hERG / QT
No hERG assay; no adverse ECG effects in monkeys at 50 or 300 mg/kg IV or 300 mg IM weekly
“In that study, ECG parameters assessed predose and 24 hours postdose on Days 1 and 29 and prior to the recovery necropsy, showed no adverse nirsevimab-related effects following 50 mg/kg IV, 300 mg/kg IV, or 300 mg IM once weekly for five total doses.”
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
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: 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.”
Anti-drug antibodies: animals
Monkey: no ADA during dosing; ADA in 4 (22.2%) recovery animals
“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).”
Anti-drug antibodies: patients
Trial 04: 5% (95/1778) ADA-positive at Day 361; 21% of these neutralizing, 77% anti-YTE
“In Trial 04, 5% (95/1778) of subjects were ADA-positive on Day 361, of whom 21% (20/95) had neutralizing antibodies and 77% (73/95) had ADA against YTE.”
Label warnings
- Hypersensitivity Reactions Including Anaphylaxis
- Use in Individuals with Clinically Significant Bleeding Disorders
Hypersensitivity & infusion reactionsBleeding
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week GLP cynomolgus monkey (IV/IM) with 25-week recovery
“Nirsevimab nonclinical safety studies included a good laboratory practice (GLP) 4-week intravenous/intramuscular repeat-dose toxicology study in cynomolgus monkeys with a 25-week recovery period”
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.”
DART package
Species: DART
Not conducted (ICH S6(R1)): exogenous viral target
“Dedicated in vivo DART studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”
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.”
PPND / ePPND: when
Not conducted: DART studies not needed for an antibody to an exogenous (viral) target (ICH S6(R1))
“Dedicated in vivo DART studies have not been conducted with nirsevimab. In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenesis, mutagenesis and reproductive toxicity studies have not been performed with BEYFORTUS.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment found 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.”
Carcinogenicity timing
Not required: non-endogenous viral target, intermittent use (ICH S6(R1))
“Thus, in accordance with ICH guideline S6(R1) the omission of carcinogenicity studies is considered acceptable.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey IM NOAEL 300 mg/week: 8-fold infant AUC, 44-fold Cmax (50/100 mg IM)
“Based on the NOAEL of 300 mg/week i.m. calculated safety margins for a dose of 50 mg i.m. for infants weighing <5 kg and 100 mg i.m. for those weighing ≥5 kg entering their first RSV season was 44-fold based on Cmax and 8-fold based on AUC.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Cotton rat RSV A2/B9320 challenge model with antibody 1G7 (IM prophylaxis 1 day before infection)
“In Zhu et al, 2017, the antiviral activity of 1G7 was investigated in vivo by administering 1G7 i.m. at 8 different dose levels to cotton rats 1 day prior to challenging with RSV A2 or RSV B9320 strains at doses up to 3 mg/kg and 1.5 mg/kg, respectively.”
Why that model
YTE Fc modification decreases antibody exposure in rodents, so parental 1G7 used for rodent pharmacology
“The YTE modification was added to the mAb to prolong the terminal half-life of the antibody in humans, though the modification significantly decreases antibody exposure in rodents resulting in decreased serum antibody levels relative to the native human Fc. Therefore, the parental molecule, 1G7, was utilized for nonclinical pharmacology studies conducted in rodents.”
Reviewer's view of the efficacy data
EMA: adequate in vitro/in vivo pharmacology including a disease model; nonclinical proof of concept established
“An adequate program of in vitro and in vivo pharmacology was conducted for nirsevimab, including a disease model, supporting the intended clinical use of nirsevimab. Non-clinical proof of concept as an antibody-mediated prophylactic treatment for the prevention of RSV seems established.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity study despite an infant indication
Why: Nature of the target and modality, and existing nonclinical knowledge · No relevant species · Low-risk modality · Weight of evidence
“Although the current indication includes very young children, the nature of the target and therapeutic modality and knowledge from conducted non-clinical studies, a juvenile study is not expected to provide any added value.”
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies
Why: Viral target not expressed endogenously; infant population excludes women of childbearing potential; no reproductive tissue effects or cross-reactivity · Within the guideline · No relevant species
“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.”
“In the absence of adverse local or systemic effects of nirsevimab and in the absence of cross-reactivity with human tissues the omission of dedicated non-clinical fertility, embryo-foetal and prenatal and postnatal development studies is supported.”
GLPCriticised but acceptedBeyond the letter
Pivotal monkey toxicity study partly non-GLP: nasal wash analysis, formulation analysis and clinical pathology report
“However, it was also noted that the formulation analysis and clinical pathology report were not conducted according to GLP. Apart from these discrepancies, the study was considered to be in compliance with GLP.”
OtherAccepted with a conditionBeyond the letter
No lung histopathology in cotton rats to assess antibody-dependent enhancement of disease
Why: Weight of evidence indicates low risk of ADE; risk monitored clinically after authorisation and included in the RMP · Weight of evidence
“Though histopathological evaluations of lung tissue were not conducted in cotton rats, which could have provided further information on the potential occurrence of alveolitis with (neutrophilic) infiltrates, which is an acknowledged marker of ADE in the cotton rat model, the overall weight of evidence presented by the Applicant indicates a low risk of ADE of disease for nirsevimab.”
“The risk of ADE will further be monitored in the clinic after marketing authorization and is included in the RMP.”
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