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

Precedia/Monoclonal antibodies/Erbitux/Tox package

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

cetuximab · EGFR

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 Erbitux 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: Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose (EMA assessment report, p. 11)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

39-week cynomolgus monkey study with treatment-free recovery period

“In the 39-week repeat-dose toxicity study in Cynomolgus monkeys, examination of individual sexual cycle length from week 25 onwards, including the treatment-free period, revealed an impairment of menstrual cyclicity in Cetuximab treated females such as increased incidences of irregular cyclicity or absence of cyclicity when compared to controls.”

✓ VerifiedEMA assessment report, p. 12Source ↗

Pivotal GLP studies

39-week IV cynomolgus study: 12/38/120 mg/kg initial dose, then weekly 7.5/24/75 mg/kg

“The initial doses and subsequent weekly doses were 12 and 7.5 mg/kg for the low dose group, 38 and 24 mg/kg for the intermediate dose group, and 120 and 75 5 mg/kg for the high dose group.”

✓ VerifiedEMA assessment report, p. 11Source ↗

DART package

Species: DART

Cynomolgus monkey (embryo-fetal development, organogenesis dosing)

“Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA).”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey embryo-fetal study: embryolethality and abortions, no fetal malformations

“While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

Not conducted: no reproductive and developmental toxicity studies performed

“No reproductive and developmental toxicity studies were performed.”

✓ VerifiedEMA assessment report, p. 12Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“No carcinogenicity studies were performed.”

✓ VerifiedEMA assessment report, p. 13Source ↗

Carcinogenicity model

Not conducted; standard carcinogenicity studies considered inappropriate for biotechnology-derived products

“No standard carcinogenicity studies were performed with cetuximab as these are generally considered inappropriate for biotechnology-derived products79.”

✓ VerifiedEMA assessment report, p. 15Source ↗

Carcinogenicity timing

Not required given life-expectancy in the advanced cancer indication

“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”

✓ VerifiedEMA assessment report, p. 15Source ↗

Summary across all 117 monoclonal antibodies →

Erbitux: 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