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

Precedia/Monoclonal antibodies/Stelara/Tox package

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

ustekinumab · IL-12/23 p40

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

IV toxicology studies in primates supported the first human dose (NOAEL 500-fold above the first dose tier)

“supported by IV toxicology studies in primates that demonstrated no observed adverse effect level at doses 500-fold higher than the first dose tier studied in humans and 10-fold higher than the highest dose studied.”

✓ VerifiedEMA assessment report, p. 24Source ↗

First-in-human starting dose

Not stated in public reviews

Why it's blank

The public FDA and EMA reviews of Stelara 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: Well tolerated at 45 mg/kg twice weekly SC for 6 months in monkeys; no target organs, no delayed toxicity (EMA assessment report, p. 18)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week SC cynomolgus monkey study with 12-week recovery

“26-week Subcutaneous Dose Toxicity and Toxicokinetic Study with CNTO 1275 (STELARA, ustekinumab) in Cynomolgus Monkeys with a 12-week Recovery Period (Study T-2001-004)”

✓ VerifiedEMA assessment report, p. 13Source ↗

Pivotal GLP studies

Cynomolgus monkey studies: IV up to 45 mg/kg weekly for 1 month; SC up to 45 mg/kg twice weekly for 6 months

“Repeat-dose toxicity studies showed that CNTO 1275 (STELARA, ustekinumab) is generally well tolerated following IV doses up to 45 mg/kg/week for up to 1 month (Studies T-099-003 and T-099-004), and following twice-weekly SC doses up to 45 mg/kg for 6 months (Study T-2001-004).”

✓ VerifiedEMA assessment report, p. 13Source ↗

DART package

Species: DART

Cynomolgus monkey and mouse

“The safety studies include repeated-dose toxicity with periods of recovery in cynomolgus monkeys, and developmental and reproductive toxicity studies in cynomolgus monkeys and mice; a number of non-pivotal studies was also conducted.”

✓ VerifiedEMA assessment report, p. 13Source ↗

Reproductive & developmental

Monkey EFD (IV or SC) and pre-/postnatal development (SC) studies: no effects on gestation, parturition, lactation or offspring

“In studies of embryo-fetal development in cynomolgus monkeys dosed intravenously or subcutaneously and pre-and post-natal development dosed subcutaneously, there were no effects on gestation, parturition, lactation or morphology or development of the offspring.”