Ztalmy
ganaxolone
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“general toxicology (up to 6 and 12 months in rat and dog), reproductive and developmental toxicology”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 12-month dog study (1245-011; oral doses of 0, 3, 10, or 15 mg/kg/day, preformulated suspension), dose-dependent clinical findings related to the sedative effect (decreased activity, tremors, ataxia, prostration, and unresponsiveness) were seen at all doses.”
Study lengthopen answer page →
Longest pivotal study
52 (12-month dog)
“In the 12-month dog study (1245-011; oral doses of 0, 3, 10, or 15 mg/kg/day, preformulated suspension), dose-dependent clinical findings related to the sedative effect (decreased activity, tremors, ataxia, prostration, and unresponsiveness) were seen at all doses.”
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.”
Route in tox
Oral
“In the second stage of development, a new formulation - not containing β-CD - was evaluated in repeat-dose toxicology studies in mice (2 weeks, dosing up to 1000 mg/kg/day), in rats (4 weeks, dosing up to 80 mg/kg/day) and in dogs (up to 12 months, dosing up to 15 mg/kg/day) using a preformulated oral GNX suspension.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat micronucleus assays; human metabolite M2 clastogenic in vitro
“Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro-ganaxolone, was negative for mutagenicity in the in vitro Ames assay but positive for clastogenicity in an in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes.”
Carcinogenicity
26-week Tg.rasH2 mouse: no tumor increase; no rat carcinogenicity 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.”
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.”
Safety pharmacology
No hERG inhibition at 10 μM; no BP, heart rate or ECG effects in dog telemetry up to 15 mg/kg
“GNX did not inhibit the hERG channel at a concentration of 10 μM (Study 1245-007) and there were no alterations in blood pressure, heart rate, or qualitative or quantitative ECG parameters in a CV safety pharmacology study in conscious, telemetered beagle dogs (Study 1245-008) up to the highest dose tested (15 mg/kg).”
First doseopen answer page →
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.”
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)
NOAEL / key findings
Dose-related reversible sedation in rats and dogs; little other target-organ or systemic toxicity
“The most common effect observed in the pivotal repeat-dose toxicology studies in adult rats and dogs was dose-related, reversible sedation, an expected pharmacological action of a positive modulator of GABAA receptors. Otherwise, there was little evidence of target organ or systemic toxicity in either species.”
Risksopen answer page →
Immune & cytokine safety
No antigenicity or immunogenicity studies conducted
“No studies for antigenicity, immunogenicity, photosafety have been conducted.”
Biodistribution & persistence
Wide distribution in rat QWBA; crosses blood-brain and testis barriers; no melanin binding
“As pigmented and non-pigmented skins were comparably labelled, it is concluded that there is no melanin binding. Radioactivity was found to cross the testis, and blood-brain barrier, and exposure was about 2-fold lower than in blood.”
Modality-specific risk
Major human metabolites M2 and M47 (~25% each of circulating drug-related material) not covered in animals
“In humans, two metabolites, M2 (oxy-dehydro-ganaxolone) and M47 (a ganaxolone sulfate conjugate), have been identified as major metabolites, each accounting for approximately 25% of total circulating drug-related material.”