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

Precedia/Small molecules/Zurzuvae/Tox package

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

zuranolone · GABA-A receptor (positive modulator)

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 Zurzuvae 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: Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure (FDA integrated review, p. 158)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

Dog oral study of 273 days including a 28-day recovery period

“An additional GLP study was conducted to evaluate the potential toxicity in dogs when zuranolone was administered at dose levels up to 2.5 mg/kg/day once daily for 273 days, including a 28-day recovery period.”

✓ VerifiedEMA assessment report, p. 29Source ↗

Pivotal GLP studies

6-month rat and 9-month dog oral studies

“Dose selection for the 6- and 9-month toxicology studies in rat and dog was based on the results of shorter-duration studies that identified clear dose-limiting toxicity, including premature death and adverse clinical signs (e.g., sedation, convulsions).”

✓ VerifiedFDA integrated review, p. 82Source ↗

DART package

Species: DART

Rat, mouse and rabbit (embryo-fetal development)

“Embryo-foetal development GLP studies were conducted in pregnant Sprague Dawley rats Crl:CD1(ICR) mice and rabbits.”

✓ VerifiedEMA assessment report, p. 31Source ↗

Reproductive & developmental

Rat EFD: malformations (exencephaly, tail, eye lens, vertebral/rib) at the high dose

“Malformations were observed in 10 HD pups (5 litters): exencephaly (1 fetus), absent tail (2 littermates), short thread-like tail and/or malformation of the sacral and caudal vertebrae (2 littermates), umbilical hernia and depressed eye bulges (1 fetus), absent or small lens of the eye (2 littermates) and vertebral/rib malformations (2 littermates).”

✓ VerifiedFDA integrated review, p. 162Source ↗

PPND / ePPND: when

Rat PPND completed before the marketing application

“Oral administration of zuranolone (0, 1, 4, or 10 mg/kg/day) to rats throughout pregnancy and into lactation resulted in increased perinatal mortality and persistent bodyweight reductions in the offspring at the mid and high doses”

✓ VerifiedFDA integrated review, p. 147Source ↗

Carcinogenicity

Species: carcinogenicity

Tg.rasH2 mouse (6-month) and rat (2-year)

“The carcinogenic potential of zuranolone was tested in a 6-month Tg.rasH2 transgenic mouse assay and in a 2-year rat carcinogenicity study. Both studies were adequately conducted and, according to the Food and Drug Administration (FDA) statistical analyses, negative for drug-induced tumors.”

✓ VerifiedFDA integrated review, p. 161Source ↗

Carcinogenicity model

6-month Tg.rasH2 mouse; 2-year rat; negative

✓ VerifiedFDA integrated review, p. 161Source ↗

Carcinogenicity timing

6-month Tg.rasH2 mouse and 2-year rat studies completed before the marketing application; both negative

✓ VerifiedFDA integrated review, p. 161Source ↗

Summary across all 211 small molecules →

Zurzuvae: 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