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

Precedia/Small molecules/Tryvio/Tox package

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

aprocitentan · Endothelin A/B receptors

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 Tryvio 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 small molecules outside oncology

Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.

“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

This product's starting point

NOAEL / key findings: NOAEL 50 mg/kg/day in rats and 5 mg/kg/day in dogs (~14- and 11-fold MRHD exposure) (FDA integrated review, p. 65)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

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

“Repeat dose toxicity studies were conducted in dogs for up to 39 weeks with oral dose levels from 5 to 1000 mg/kg/day. Key findings are summarized below. 39-Week (13-Week Recovery) Toxicology Study”

✓ VerifiedFDA integrated review, p. 134Source ↗

Pivotal GLP studies

26-week rat and 39-week dog repeat-dose studies

“General toxicity studies were conducted for durations up to 26 weeks in rats and 39 weeks in dogs.”

✓ VerifiedFDA integrated review, p. 66Source ↗

DART package

Species: DART

Rat and rabbit (EFD with aprocitentan alone)

“No embryo-fetal toxicity was observed in the EFD studies with aprocitentan alone at 5-fold and 29-fold the human exposure at the MRHD in rats and rabbits, respectively.”

✓ VerifiedFDA integrated review, p. 64Source ↗

Reproductive & developmental

Macitentan rat and rabbit EFD: teratogenic at all doses, no NOAEL; risk extrapolated to aprocitentan

“In embryo-fetal developmental (EFD) toxicity studies, treatment with macitentan (for which aprocitentan is a major metabolite) in pregnant rats and rabbits revealed teratogenicity and developmental toxicity at all doses tested, and therefore a no observed adverse effect level (NOAEL) for embryo fetal toxicity in the rat and rabbits could not be established.”

✓ VerifiedFDA integrated review, p. 64Source ↗

PPND / ePPND: when

PPND in rat with macitentan (parent drug) completed before the marketing application

“In a pre- and postnatal developmental study in female rats, oral administration of 10, 50 or 250 mg/kg/day macitentan during the pregnancy and the lactational periods reduced pup survival and impaired male fertility of offspring at all doses.”

✓ VerifiedFDA integrated review, p. 64Source ↗

Carcinogenicity

Species: carcinogenicity

Mouse and rat 2-year studies with macitentan (aprocitentan's parent drug)

“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”

✓ VerifiedFDA integrated review, p. 67Source ↗

Carcinogenicity model

2-year mouse and rat with macitentan: negative (~30x and 11x aprocitentan AUC at MRHD)

✓ VerifiedFDA integrated review, p. 67Source ↗

Carcinogenicity timing

2-year mouse and rat studies with macitentan (parent drug) completed before the marketing application

“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats”

✓ VerifiedFDA integrated review, p. 67Source ↗

Summary across all 211 small molecules →

Tryvio: 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