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

Precedia/Small molecules/Truqap/Tox package

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

capivasertib · AKT1-3

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 Truqap 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: Targets: insulin signaling, cardiovascular system, male reproductive organs, liver, kidney, HPA axis, hematopoietic system (FDA multi-discipline review, p. 47)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

9-month dog (oral), no recovery group

“it is acknowledged that cardiac effects were not noticed in the 9-months dog study and no safety signal in clinical studies were observed; however this study did not include a recovery group (similar to the long-term rat study).”

✓ VerifiedEMA assessment report, p. 41Source ↗

Pivotal GLP studies

Oral GLP studies up to 6 months in rats and 9 months in dogs

“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”

✓ VerifiedFDA multi-discipline review, p. 46Source ↗

DART package

Species: DART

Rat only (combined preliminary EFD and pre/postnatal study)

“In a GLP-compliant preliminary embryofetal development and pre- and post-natal study, capivasertib was administered at doses of 10, 30 and 150 mg/kg/day to pregnant rats from Day 2 to Day 16 of gestation (Phase 1) or from Day 6 of gestation to at least Day 6 of lactation (Phase 2).”

✓ VerifiedFDA multi-discipline review, p. 48Source ↗

Reproductive & developmental

Rat preliminary EFD: post-implantation loss, minor visceral variations and reduced fetal weights at 150 mg/kg/day

“Administration of capivasertib to rats prior to implantation until Day 16 of gestation resulted in minor fetal visceral variations, an increase in post-implantation loss, and reduced gravid uterine and fetal weights at 150 mg/kg/day.”

✓ VerifiedFDA multi-discipline review, p. 48Source ↗

PPND / ePPND: when

Combined preliminary EFD and PPND study in rat completed before the marketing application

“Preliminary studies on embryonic and foetal development in rats and a pre- and postnatal study have been carried out.”

✓ VerifiedEMA assessment report, p. 43Source ↗

Carcinogenicity

Species: carcinogenicity

Rat (2-year)

“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

2-year rat, up to 30 (males) and 75 (females) mg/kg/day, ~0.2x and 0.4x human AUC

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

Not conducted: not warranted for an advanced cancer indication

“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Summary across all 211 small molecules →

Truqap: 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