Zulresso
brexanolone
Species
RatDog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
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
“Sedative anesthesia was observed rapidly after single bolus IV doses of brexanolone in rats and dogs at 0.75- and 2-times, respectively, the MRHD based on body surface area, which were the lowest doses tested.”
Species: general tox
Rat and dog
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Species: DART
Rat and rabbit
“Reproductive and developmental toxicity was observed with brexanolone administration in rats and rabbits.”
Species: carcinogenicity
Not conducted (short-term treatment, 2.5 days)
“Because brexanolone use for PPD is considered a short-term treatment (2.5 days), carcinogenicity studies were not conducted.”
Surrogate used in
No surrogate used
“Sedative anesthesia was observed rapidly after single bolus IV doses of brexanolone in rats and dogs at 0.75- and 2-times, respectively, the MRHD based on body surface area, which were the lowest doses tested.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Pivotal GLP studies
28-day continuous IV infusion studies in rat and dog
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Route in tox
Continuous intravenous infusion
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays
“Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (acute treatment of PPD)
“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”
Reproductive & developmental
Rat and rabbit EFD: no malformations up to 5-6x MRHD; developmental toxicity at 5x (rat) and >=3x (rabbit)
“In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively.”
Safety pharmacology
CNS (rat FOB) and cardiovascular/respiratory (dog) endpoints embedded in 14-day toxicology studies
“CNS safety pharmacology was evaluated as part of the 14-day rat toxicology study using a Functional Observation Battery (FOB). Cardiovascular and respiratory safety pharmacology was evaluated as part of the 14-day dog toxicology study”
Genotox: Ames
Negative (Ames)
“SAGE-547 was negative for mutagenicity in bacterial cells in a valid Ames test.”
Genotox: in vitro mammalian
In vitro human lymphocyte micronucleus: negative
“SAGE-547 was negative for clastogenicity in human lymphocytes in a valid in vitro micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative at 34x clinical exposure
“SAGE-547 was not clastogenic in a valid in vivo micronucleus assay at plasma concentrations 34-times clinical exposure.”
Carcinogenicity model
Not conducted (short-term treatment, 2.5 days)
“Because brexanolone use for PPD is considered a short-term treatment (2.5 days), carcinogenicity studies were not conducted.”
Carcinogenicity timing
Not required; acute treatment of postpartum depression
“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”
hERG / QT
hERG IC50 >6.6 µM (solubility-limited), >28x clinical exposure at MRHD
“IC50 > 6.6 µM (SAGE-547 insoluble in assay vehicle at higher concentrations), which is greater than 28-times the clinical exposures at the MRHD.”
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 Zulresso 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: Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD) (FDA multi-discipline review, p. 46)
NOAEL / key findings
Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD)
“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure”
Risksopen answer page →
Immune & cytokine safety
No dermal irritation, skin sensitization or hemolytic potential
“In addition, brexanolone showed no sign of dermal irritation, skin sensitization, or hemolytic potential.”
Biodistribution & persistence
CNS tissue radioactivity above blood levels; low levels in testis
“Radioactivity concentrations were observed in CNS tissues at higher than blood concentrations and in testis at low levels.”
Modality-specific risk
Post-infusion convulsions in dogs, possibly from abrupt discontinuation of GABA-A modulation
“It is possible that the convulsions could be due to the rapid discontinuation of brexanolone, which is consistent with modulation of the GABAA receptor”
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 Not applicable to this application.”
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 Zulresso 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: Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD) (FDA multi-discipline review, p. 46)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day continuous IV infusion studies in rat and beagle dog, each with 28-day recovery
“A 28-Day Study of SAGE-547 by Intravenous Infusion in Beagle Dogs with a 28-Day Recovery Period”
Pivotal GLP studies
28-day continuous IV infusion studies in rat and dog
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
DART package
Species: DART
Rat and rabbit
“Reproductive and developmental toxicity was observed with brexanolone administration in rats and rabbits.”
Reproductive & developmental
Rat and rabbit EFD: no malformations up to 5-6x MRHD; developmental toxicity at 5x (rat) and >=3x (rabbit)
“In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively.”
PPND / ePPND: when
Rat PPND (continuous IV infusion) completed and reviewed with the marketing application
“A Continuous Intravenous Infusion Pre and Postnatal Study of SAGE-547 in the Rat”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-term treatment, 2.5 days)
“Because brexanolone use for PPD is considered a short-term treatment (2.5 days), carcinogenicity studies were not conducted.”
Carcinogenicity model
Not conducted (short-term treatment, 2.5 days)
“Because brexanolone use for PPD is considered a short-term treatment (2.5 days), carcinogenicity studies were not conducted.”
Carcinogenicity timing
Not required; acute treatment of postpartum depression
“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 60 mg/kg/day ~5x human AUC at MRHD (90 µg/kg/h)
“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure (AUC24h = 1800 ng.h/mL; Css = 74.3 ng/mL) at the MRHD of 90 μg/kg/h.”
NOAEL / key findings
Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD)
“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure”
Efficacy evidenceopen answer page →
Efficacy evidence
Behavioral depressant effects (sedation, muscle relaxation, decreased locomotion) in rats, dogs and mice; no PPD model
“In general animal behavioral studies, brexanolone produces dose-dependent depressant effects such as sedation and muscle relaxation in rats and dogs and decreased locomotion in mice.”
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
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.
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No carcinogenicity studies
Why: Treatment of postpartum depression by infusion is acute · Within the guideline
“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”
Juvenile toxAccepted with a conditionBeyond the letter
Developmental neurotoxicity (apoptotic neurodegeneration) of GABAergic drugs not studied with brexanolone; animal study required post-marketing
Why: Unclear threshold for apoptotic neurodegeneration; post-marketing animal study to inform labeling
“Although allopregnanolone is an endogenous neuroactive steroid, it is not clear if there is a threshold effect above which increased apoptotic neurodegeneration would occur.”
“Additionally, a postmarketing requirement (PMR) to conduct an animal study to determine if these effects will be observed with brexanolone to allow for appropriate labeling and to reflect any risks to patients has been requested and accepted by the Applicant.”
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