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

Precedia/Small molecules/Truseltiq/Tox package

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

infigratinib · FGFR1-3

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 Truseltiq 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 small molecules (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: Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat) (FDA multi-discipline review, p. 43)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

39-week dog (oral gavage) with 13-week recovery

“BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period”

✓ VerifiedFDA multi-discipline review, p. 56Source ↗

Pivotal GLP studies

26-week rat and 39-week dog oral studies

“After 26 or 39 weeks of infigratinib administration in rats and dogs, respectively, the main target organ was bone.”

✓ VerifiedFDA multi-discipline review, p. 50Source ↗

DART package

Species: DART

Rat and rabbit (embryo-fetal development); no pre/postnatal study

“The potential maternal and embryo‐fetal developmental effects of infigratinib after once‐daily dosing was evaluated in female Wistar Han rats and female New Zealand White rabbits.”