Beyfortus (nirsevimab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Beyfortus/Tox package

Beyfortus: what was done before first-in-human, and what came after?

nirsevimab · RSV F protein

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.”

✓ VerifiedEMA 2017: Guideline on strategies to identify and mitigate risks for…, p. 11Source ↗

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)

Full method, every step sourced →

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”

✓ VerifiedFDA integrated review, p. 120Source ↗

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.”

✓ VerifiedEMA assessment report, p. 33Source ↗

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.”

✓ VerifiedFDA integrated review, p. 162Source ↗

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.”

✓ VerifiedEMA assessment report, p. 33Source ↗

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.”

✓ VerifiedFDA integrated review, p. 162Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“Carcinogenesis, mutagenesis and reproductive toxicity studies have not been performed with BEYFORTUS.”

✓ VerifiedUS prescribing informationSource ↗

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.”

✓ VerifiedFDA integrated review, p. 162Source ↗

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.”

✓ VerifiedEMA assessment report, p. 33Source ↗

Summary across all 117 monoclonal antibodies →

Beyfortus: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Email me this as a cited memo

Same question, other monoclonal antibodies