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

Precedia/Small molecules/Vanrafia/Tox package

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

atrasentan · Endothelin A receptor

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

First-in-human single-dose study started at 139.5 mg; derivation not described

“Initially, the study was designed as a single dose, dose-escalating study with the starting dose of 139.5 mg.”

✓ VerifiedFDA integrated review, p. 140Source ↗

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

39-week (9-month) beagle dog with recovery groups (control and high dose); recovery length not stated

“Methods: Animals were dosed by oral administration for 9 months. Dose and frequency of dosing: 10, 30, 100 mg/kg/day Route of administration: Oral Formulation/vehicle: Atrasentan HCl powder in gelatin capsules. Species/strain: Beagle dog Number/sex/group: Five/sex/dose group Age: 6.5 to 7.5 months old Satellite groups: Recovery: two/sex (control and high-dose group)”

✓ VerifiedFDA integrated review, p. 121Source ↗

Pivotal GLP studies

26-week rat and 39-week dog studies

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

✓ VerifiedFDA integrated review, p. 64Source ↗

DART package

Species: DART

Rat and rabbit (embryo-fetal development)

“In embryo-fetal developmental toxicity studies, treatment with atrasentan in pregnant rats and rabbits revealed teratogenicity”

✓ VerifiedFDA integrated review, p. 63Source ↗

Reproductive & developmental

Rat and rabbit EFD: teratogenic at exposures below the MRHD

“In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

Rat PPND (GLP) completed and reviewed in the NDA

“13.1.7.3. Pre- and Postnatal Developmental Study Study Number/Title: R&D/15/0589 Peri- and Postnatal Development in Rats GLP compliance: Yes”

✓ VerifiedFDA integrated review, p. 130Source ↗

Carcinogenicity

Species: carcinogenicity

Sprague Dawley rat (104-week) and Tg rasH2 mouse (26-week)

“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”

✓ VerifiedFDA integrated review, p. 124Source ↗

Carcinogenicity model

104-week rat; 26-week Tg rasH2 mouse

✓ VerifiedFDA integrated review, p. 124Source ↗

Carcinogenicity timing

104-week Sprague Dawley rat and 26-week Tg(HRAS)2Jic (rasH2) mouse completed before the marketing application

✓ VerifiedFDA integrated review, p. 124Source ↗

Summary across all 211 small molecules →

Vanrafia: 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