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

Precedia/Monoclonal antibodies/Pasatru/Tox package

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

garetosmab · Activin A

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 Pasatru 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: Cynomolgus monkey NOAEL 50 mg/kg for both sexes (highest dose; about five-times clinical AUC) (FDA integrated review, p. 59)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey IV study (weekly, up to 50 mg/kg) with treatment-free recovery period

“in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg (14 times or 49 times the recommended human doses of garetosmab 3 mg/kg or 10 mg/kg every 4 weeks, respectively, based on AUC). Minimal to moderate seminiferous tubule degeneration was observed in male monkeys, which was reversible after a treatment-free recovery period.”

✓ VerifiedFDA integrated review, p. 111Source ↗

Pivotal GLP studies

Cynomolgus monkey 26-week IV study, once weekly, up to 50 mg/kg, with reproductive organ and fertility endpoints

“Reproductive organs and fertility-related parameters were assessed in sexually mature cynomolgus monkeys in a 26-week study in which garetosmab was administered intravenously once weekly at doses up to 50 mg/kg”

✓ VerifiedFDA integrated review, p. 111Source ↗

DART package

Species: DART

Cynomolgus monkey (enhanced pre- and postnatal development); no dedicated fertility studies

“In an enhanced pre- and postnatal development study in cynomolgus monkeys, weekly intravenous infusion of garetosmab at 5 or 50 mg/kg from gestation Day 20 until delivery resulted in no maternal toxicity.”

✓ VerifiedFDA integrated review, p. 60Source ↗

Reproductive & developmental

Monkey ePPND: severe developmental toxicity at 50 mg/kg with 100% offspring mortality by postnatal day 6

“Severe developmental toxicity occurred at 50 mg/kg (approximately nine-times the maximum clinical exposure based on AUC), with 100% mortality of all spontaneously delivered offspring by postnatal Day 6.”

✓ VerifiedFDA integrated review, p. 60Source ↗

PPND / ePPND: when

ePPND in cynomolgus monkey (IV 5 or 50 mg/kg weekly) completed before the marketing application

✓ VerifiedFDA integrated review, p. 60Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted; weight-of-evidence carcinogenicity assessment

“Carcinogenicity studies have not been conducted with garetosmab-grts.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Not conducted; weight-of-evidence carcinogenicity assessment instead

“a weight of evidence carcinogenicity assessment, and tissue cross-reactivity studies.”

✓ VerifiedFDA integrated review, p. 58Source ↗

Carcinogenicity timing

Not conducted

“Carcinogenicity studies have not been conducted with garetosmab-grts.”

✓ VerifiedUS prescribing informationSource ↗

Summary across all 117 monoclonal antibodies →

Pasatru: 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