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

Precedia/Small molecules/Ztalmy/Tox package

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

ganaxolone · 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 Ztalmy 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: Dose-related reversible sedation in rats and dogs; little other target-organ or systemic toxicity (FDA pharmacology/toxicology review, p. 112)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

1-year oral dog study; recovery not stated

“Ganaxolone: A 1-Year Oral Toxicity Study in Dogs”

✓ VerifiedFDA pharmacology/toxicology review, p. 51Source ↗

Pivotal GLP studies

6-month Sprague Dawley rat and 12-month beagle dog studies

“The primary drug-related toxicity observed in the general toxicology studies of duration up to 6 and 12 months in Sprague Dawley (SD) rat and beagle dog, respectively, was sedation, which in some cases was associated with death or premature sacrifice.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

DART package

Species: DART

Rat (fertility, combined EFD/pre- and postnatal) and mouse (EFD)

“developmental toxicology (fertility and early embryonic development in rat, embryofetal development in mouse, and combined embryofetal/pre- and postnatal development in rat)”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Reproductive & developmental

Mouse EFD: external/visceral fetal malformations at all doses without maternal toxicity

“In the EFD study in mouse, an increase in fetal malformations (external, visceral) was observed at all doses (0, 50, 175, and 300 mg/kg/day) in the absence of maternal toxicity.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

PPND / ePPND: when

Combined EFD/PPND study in SD rat completed before the marketing application

“A full battery of reproductive and developmental toxicology studies was conducted for ganaxolone: fertility and early embryonic development (FEED) study in SD rat, embryofetal development (EFD) study in CD-1 mouse, and a combined EFD/pre- and postnatal development (PPND) study in SD rat.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

Carcinogenicity

Species: carcinogenicity

Tg.rasH2 mouse (26 weeks); no rat study conducted

“Oral administration of ganaxolone (150, 500, and 1000 mg/kg/day in males and 100, 300, and 1000 mg/kg/day in females) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. No carcinogenicity studies have been conducted with ganaxolone in rats.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

26-week TgRasH2 mouse and 2-year rat, required as postmarketing studies

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR)”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Carcinogenicity timing

26-week TgRasH2 mouse and 2-year rat studies to be conducted after approval (PMR)

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR)”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Summary across all 211 small molecules →

Ztalmy: 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