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.”
Species: general tox
Sprague Dawley rat (6 months) and beagle dog (12 months)
“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.”
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)”
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.”
Surrogate used in
No surrogate used; ganaxolone tested directly
“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.”
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).”
Genotox: Ames
Negative (ganaxolone and metabolite M2)
“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”
Genotox: in vitro mammalian
Ganaxolone negative in mouse lymphoma; major metabolite oxy-dehydro-ganaxolone (M2) positive in human lymphocyte chromosomal aberration test
“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.”
Genotox: in vivo
Rat micronucleus negative (ganaxolone up to 140 mg/kg)
“GNX was evaluated in a GLP-compliant Ames test, in vitro mouse lymphoma cell mutagenesis assay and in vivo micronucleus assay in rats dosed with GNX up to 140 mg/kg, and demonstrated no genotoxic potential.”
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)”
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)”
hERG / QT
No significant hERG inhibition up to 10 µM (~11-fold total clinical Cmax of ~300 ng/mL)
“In two GLP-compliant in vitro hERG inhibition studies, no significant hERG inhibition was observed with GNX at concentrations up to 10 µM, which is approximately 11-fold the total GNX concentration at the clinical Cmax of ~300 ng/ml.”
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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Somnolence and Sedation
- Suicidal Behavior and Ideation
- Withdrawal of Antiepileptic Drugs
Psychiatric
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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.”
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)
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”
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.”
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)”
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.”
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.”
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.”
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)”
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)”
Safety marginopen answer page →
Safety margin at NOAEL
Exposure 6.01-7.85-fold clinical at highest tested dose (15 mg/kg/day) in 12-month dog study
“dogs' 12-month repeat-dose toxicity study, exposure margins reached 6.01-7.85 fold at the highest tested dose of 15 mg/kg/day.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Traditional rodent seizure models (chemically induced convulsions, corneal kindling); not tested in a Cdkl5 disease model
“GNX (IP or oral) was active in several traditional rodent seizure models (eg, chemically-induced convulsions, corneal kindling). GNX was not tested for activity in a Cdkl5 disease model.”
Why that model
Cdkl5 knockout mouse models do not exhibit overt seizures
“While Cdkl5 knockout mouse models have been generated, these do not exhibit overt seizures.”
Reviewer's view of the efficacy data
EMA: proof of concept that ganaxolone protects against convulsions adequately demonstrated in several seizure models
“GNX demonstrated potent, broad, GABAA-mediated anticonvulsant activity in several types of seizure models tested. The proof of concept that GNX is protective of convulsion is adequately demonstrated.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Mouse and rat carcinogenicity studies not conducted before approval; deferred to postmarketing requirements as agreed with the Division
Why: Severity of the indication · Serious disease
“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), as agreed to by the Division (IND 44020 Type C Meeting Minutes, January 11, 2018)”
“I agree with Dr. Fisher that the nonclinical studies of ganaxolone are adequate to support approval of the NDA from a nonclinical standpoint, considering the severity of the indication, with appropriate labeling and the following post-marketing requirements:”
Impurity or metaboliteAccepted with a conditionBeyond the letter
Major human metabolite M47 not characterized in animal plasma; metabolite safety evaluation deferred to postmarketing studies
Why: Metabolite M2 carcinogenicity and juvenile studies and M47 brain distribution study required postmarketing
“There is currently no information on plasma levels of M47 in animal species. Although M47 is a sulfate conjugate, there are concerns that it may have pharmacological activity, depending on the extent of its distribution into the CNS (Hartneck C. Molecules 18:12012-12028, 2013). The nonclinical safety of these metabolites is to be addressed in studies conducted as PMRs.”
“a 6-month carcinogenicity study of ganaxolone in TgRasH2 mouse, a 2-year carcinogenicity study of ganaxolone in rat, a carcinogenicity study of metabolite M2 in rat, a juvenile animal toxicology study of metabolite M2 in rat, and a study to evaluate the distribution of metabolite M47 into brain in rat.”
DARTVerdict not stated
No rabbit embryo-fetal study because sufficiently high plasma exposures could not be achieved
Why: Sufficiently high plasma exposures could not be achieved in rabbit · Pharmacology or kinetics
“(An EFD study was not conducted in rabbit because sufficiently high plasma exposures could not be achieved.)”
Safety marginVerdict not stated
No toxicokinetics in the rat embryo-fetal/pre- and postnatal study; dam exposures likely below human exposure at all doses
“Although TK data are not available for these studies, data from separate studies in SD rat suggest that plasma exposures in dams were lower at all doses tested than those in humans at the maximum recommended human dose of 1800 mg/day.”
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