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

Precedia/Monoclonal antibodies/Vectibix/Tox package

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

panitumumab · 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 Vectibix 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 toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths (EMA assessment report, p. 9)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

6-month cynomolgus monkey (IV, once weekly); recovery phase not stated

“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”

✓ VerifiedEMA assessment report, p. 8Source ↗

Pivotal GLP studies

Monkey IV studies of 4 weeks to 6 months, once-weekly dosing

“These studies had a dosing duration from 4 weeks to 6 months, and all used once-a-week dosing.”

✓ VerifiedEMA assessment report, p. 8Source ↗

DART package

Species: DART

Cynomolgus monkey (embryo-fetal study dosed during organogenesis, GD 20-50)

“Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50).”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey EFD: embryolethality and abortions at 1.25-5x human dose, no teratogenicity

“There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

No pre- and postnatal development study conducted

“No pre- and post-natal development animal studies have been conducted with panitumumab.”

✓ VerifiedEMA assessment report, p. 12Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Not conducted

“No carcinogenicity or mutagenicity studies of panitumumab have been conducted.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

No carcinogenicity studies conducted

“No carcinogenicity studies have been conducted.”

✓ VerifiedEMA assessment report, p. 10Source ↗

Summary across all 117 monoclonal antibodies →

Vectibix: 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