Zurzuvae
zuranolone
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The toxicologic and toxicokinetic (TK) profile of orally administered zuranolone was assessed in a series of single and repeat dose studies in rats and dogs for up to 6 and 9 months, respectively.”
Why that species
Metabolite coverage: all human metabolites above 1% also detected in rat or dog plasma
“All human metabolites detected at greater than 1% of drug, were also detected in rat or dog plasma.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”
Species: general tox
Rat (6-month) and dog (9-month)
“The toxicologic and toxicokinetic (TK) profile of orally administered zuranolone was assessed in a series of single and repeat dose studies in rats and dogs for up to 6 and 9 months, respectively.”
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.”
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.”
Surrogate used in
No surrogate used
“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”
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).”
Route in tox
Oral gavage
“The toxicological assessment is based on in single and repeated dose oral (gavage) toxicity studies in rats and dogs, in vitro and in vivo genotoxicity tests, reproduction and developmental toxicity studies in rabbits and/or rats, juvenile toxicity studies using rats, carcinogenicity studies in rats and transgenic mice, and studies to assess abuse liability and dependence potential.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”
Carcinogenicity
6-month Tg.rasH2 mouse and 2-year rat: negative for drug-induced tumors
“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.”
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).”
Safety pharmacology
Full CNS, cardiovascular, respiratory and ion-channel battery; hERG IC20 2.43 µM, ~10x human Cmax
“A complete battery of safety pharmacology studies (CNS, cardiovascular, respiratory, hERG channel, and cardiac ion channel assays) was conducted. In the in vitro hERG assay, the IC20 for inhibition by zuranolone was 2.43µM, which is approximately 10 times the human steady-state maximum plasma concentration (Cmax).”
Genotox: Ames
Negative (Ames)
“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”
Genotox: in vitro mammalian
In vitro chromosomal aberration: negative
“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”
Carcinogenicity model
6-month Tg.rasH2 mouse; 2-year rat; negative
“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.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat studies completed before the marketing application; both negative
“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.”
hERG / QT
No significant hERG inhibition at 3 µM (23%), above clinical Cmax
“Nevertheless, at the highest concentration evaluated (3 µM) no significant hERG channel inhibition was observed (23%), while this was sufficiently higher than the clinical Cmax.”
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 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.”
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)
NOAEL / key findings
Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure
“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
High brain penetration; brain:plasma ratio 2.23 (mouse) and 3.22 (rat)
“The brain to plasma ratio of zuranolone was 2.23 after IP injection (1 mg/kg) (SSN-868) in male mice and 3.22 (Study No. SSN-01237) after oral administration in male rats.”
Modality-specific risk
CNS: convulsions and deaths in dogs, including after dosing stopped
“Deaths, convulsions, and increased severity of clinical signs occurred in some dogs prior to a scheduled daily dose or some period after the previous dose (e.g., during a dosing holiday or recovery period after the end of dosing).”
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 applicable
“Immunogenicity Assessment—Impact of PK/PD, Efficacy, and Safety Not Applicable.”
Label warnings
Boxed warning: Impaired ability to drive or engage in other potentially hazardous activities
- Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities
- Central Nervous System Depressant Effects
- Suicidal Thoughts and Behavior
- Embryo-fetal Toxicity
NeurotoxicityPsychiatricEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 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.”
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)
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.”
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).”
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.”
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).”
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”
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.”
Carcinogenicity model
6-month Tg.rasH2 mouse; 2-year rat; negative
“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.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat studies completed before the marketing application; both negative
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 3x (males) and 2x (females) MRHD exposure (50 mg)
“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”
NOAEL / key findings
Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure
“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent anticonvulsant, EEG, anxiolytic-like and sedation models (target engagement)
“PD target engagement was also studied in rodent models of anticonvulsant, electroencephalographic, anxiolytic-like, and sedative activity consistent with the GABAA receptor PAM mechanism.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: predictable pharmacodynamic profile (anticonvulsant, anxiolytic-like, sedative) in rodent models
“Zuranolone, a GABAA receptor PAM under development for PPD and MDD, exhibits a predictable pharmacodynamic profile with anticonvulsant, anxiolytic-like, and sedative effects in rodent models.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
Rabbit embryofetal study inadequate (plasma exposure below detection in some dams); second-species study required postapproval
“Potential adverse effects of zuranolone on embryofetal development in pregnant rabbits were not adequately assessed because TK data in satellite animals demonstrated that plasma exposures in some dams were below the limit of detection.”
“As a result, the Agency requires the Applicant to conduct an adequate embryofetal development study in a second species, other than rat, to completely evaluate the potential toxicity during organogenesis and fulfil the nonclinical study requirements for embryofetal development.”
CarcinogenicityAcceptedBeyond the letter
Mouse and rat carcinogenicity studies reached only about 4- to 5-fold human exposure; higher doses limited by sedation
Why: Short-term treatment; no tumour increase at achievable exposures · Pharmacology or kinetics · Other reason
“In both species the exposure was limited (around 4-fold human exposure in mouse and 4 to 5-fold in rats) but higher doses were not achievable due to pharmacological effects of sedation.”
“At these exposures, no increase in tumour incidence was observed in either species, as compared to control groups. Carcinogenic risk of zuranolone is low, and not relevant for the current indication as the duration of treatment is short term.”
Safety marginAcceptedBeyond the letter
Dog studies: sedation below clinical exposure; doses limited by sedation
Why: Higher doses not achievable due to the sedative effect · Pharmacology or kinetics
“Sedation was seen at exposures below the clinical exposure, and tremors were seen at about 5.5-fold the clinical exposure. Higher doses were not achievable due to the sedative effect, but is considered sufficient.”
Juvenile toxCriticised but acceptedBeyond the letter
Neonatal rat (PND 7) apoptotic neurodegeneration with low margin (1.4-fold at no-effect dose)
Why: Indication restricted to women after childbirth · Other reason
“In a juvenile rat study with a single dose at PND 7, which corresponds to brain development at the end of the third trimester in humans, apoptotic neurodegeneration in one area of the brain (subiculum) in both males and females was seen. The safety margin is low (1.4-fold at NOEAL).”
“This risk is sufficiently mitigated by the change in indication, which now only includes women after childbirth.”
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