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

Precedia/Small molecules/Turalio/Tox package

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

pexidartinib · CSF1R

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 Turalio 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: Liver: hemosiderin, necrotizing inflammation and raised AST/ALT at ≥20 mg/kg (~0.6x clinical exposure) (FDA multi-discipline review, p. 40)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

9-month dog (oral gavage) with 16-week recovery

“A 9-month oral (gavage) toxicity study of PLX3397 with a 16-week recovery period in Beagle dogs”

✓ VerifiedFDA multi-discipline review, p. 54Source ↗

Pivotal GLP studies

6-month rat and 9-month dog oral GLP studies

“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

DART package

Species: DART

Rat and rabbit (embryo-fetal development)

“The Applicant conducted embryo-fetal development studies in rats and rabbits.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Reproductive & developmental

EFD: malformations, post-implantation loss and abortion at maternal exposures about equal to human exposure

“Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure at the recommended dose (see Data ) .”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

PPND in rat completed before the marketing application

“In a pre-and postnatal development study, female rats received pexidartinib once daily from GD 6 to lactation day (LD) 20 at doses up to 10 mg/kg/day (approximately 0.3 times the exposure at the 800 mg clinical dose).”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Carcinogenicity

Species: carcinogenicity

Rat (2-year) and Tg rasH2 mouse (26-week)

“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”

✓ VerifiedFDA multi-discipline review, p. 60Source ↗

Carcinogenicity model

2-year rat; 26-week rasH2 transgenic mouse: negative

“The Applicant also conducted a two-year (104-week) carcinogenicity study in rats and a 26-week carcinogenicity study in transgenic mice. Pexidartinib was negative for carcinogenicity in these studies.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Carcinogenicity timing

2-year rat and 26-week rasH2 mouse studies completed before the marketing application

“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”

✓ VerifiedFDA multi-discipline review, p. 60Source ↗

Summary across all 211 small molecules →

Turalio: 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 small molecules