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

Precedia/Monoclonal antibodies/Margenza/Tox package

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

margetuximab · HER2

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 Margenza 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.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

This product's starting point

NOAEL / key findings: NOAEL 150 mg/kg/dose (highest dose) after 6 weekly IV doses in monkeys (FDA multi-discipline review, p. 43)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week cynomolgus monkey (weekly IV infusion) GLP study with 10-week recovery

“13-Week GLP intravenous infusion chronic toxicity study with margetuximab in cynomolgus monkeys with a 10-week recovery (Study 8321179)”

✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Pivotal GLP studies

GLP cynomolgus monkey 6-week (up to 150 mg/kg/dose) and 13-week (up to 100 mg/kg/dose) repeat-dose studies

“The Applicant conducted GLP-compliant 6-week (doses up to 150 mg/kg/dose) and 13-week (doses up to 100 mg/kg/dose) repeat-dose toxicology studies of margetuximab in cynomolgus monkeys.”

✓ VerifiedFDA multi-discipline review, p. 37Source ↗

DART package

Species: DART

Cynomolgus monkey (enhanced pre- and postnatal development study); no fertility or early embryonic studies

“An enhanced pre- and postnatal development (ePPND) study was conducted in cynomolgus monkeys (Report 8329256) to evaluate potential effects of margetuximab on pregnancy, embryo-fetal development, parturition, and postnatal development.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Reproductive & developmental

Monkey ePPND: oligohydramnios at 50 and 100 mg/kg from GD 75; infant death at 100 mg/kg

“Treatment with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75. An infant mortality occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

ePPND in cynomolgus monkey: completed and submitted with the marketing application

“The Applicant conducted a GLP-compliant enhanced pre- and postnatal development (ePPND) toxicology study in pregnant cynomolgus monkeys.”

✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (ICH S6(R1), S1A, S9)

“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Carcinogenicity model

Not conducted (ICH S6(R1), S1A, S9; advanced cancer)

“Not performed per ICH S6(R1), ICH S1A, and ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Carcinogenicity timing

Not required for the proposed indication (FDA agreed)

“FDA agrees that carcinogenicity studies are not needed to support approval of Margenza for the proposed indication.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Summary across all 117 monoclonal antibodies →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies