Cypsedo
cipepofol
Sources:FDA multi-discipline review ↗
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
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
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
“Overall, the nonclinical safety studies conducted with cipepofol have characterized the toxicological profile of the drug product.”
Species: general tox
Rat and dog (14- and 28-day, every-other-day IV)
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
Species: DART
Rat and rabbit (embryo-fetal development); rat (pre- and postnatal)
“In the embryo-fetal developmental studies, cipepofol was not detected in the plasma of fetal rats or rabbits on Gestation Day 20 or Gestation Day 29, respectively. In the pre- and postnatal toxicity study, the test article was detected in milk samples from F0 females.”
Species: carcinogenicity
Not conducted (not required for acute use)
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
Surrogate used in
No surrogate used; studies conducted with cipepofol
“Overall, the nonclinical safety studies conducted with cipepofol have characterized the toxicological profile of the drug product.”
Study lengthopen answer page →
Longest pivotal study
4 (rat and dog, dosing every other day)
“No drug accumulation was observed in rats and beagle dogs after 7 or 14 injections given every other day over 2 or 4 consecutive weeks, respectively.”
Pivotal GLP studies
28-day rat and dog studies with every-other-day dosing (plus 14-day studies)
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
Route in tox
Intravenous bolus injection
“while all the repeat-dose studies with IV bolus injections reached Cmax levels that were much lower than the human Cmax at the HID”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and mouse bone marrow micronucleus assays
“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”
Carcinogenicity
Not conducted
“The carcinogenic potential of cipepofol has not been evaluated.”
Reproductive & developmental
Rat FEED: increased post-implantation loss from resorptions, likely related to maternal hypoxia secondary to anesthesia
“It appears that the significantly increased post-implantation loss was mainly driven by increased resorption. Similar, but not significant and not dose-dependent, effects were observed in the FEED study in rats with every other day IV dosing. The reproductive effects observed in the FEED studies are likely related to maternal hypoxia secondary to anesthesia.”
Safety pharmacology
Dog CV study: transient hypotension and QTcF increase during anesthesia
“Temporary cardiovascular (CV) effects during anesthesia, including reduced blood pressure and ECG changes such as an increase in QTcF, were observed in the cardiovascular safety pharmacology study and a single-dose toxicology study in dogs.”
Genotox: Ames
Negative
“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”
Genotox: in vitro mammalian
In vitro chromosomal aberration assay: negative
“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”
Carcinogenicity model
Not conducted (acute-use indication)
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
Carcinogenicity timing
Not required for an acute-use product
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
hERG / QT
Dog QTcF increase during anesthesia, at or below human exposure at maximum induction dose
“Temporary cardiovascular effects during anesthesia, including reduced blood pressure and electrocardiogram (ECG) changes such as an increase in QTcF interval, were observed in the cardiovascular safety pharmacology study and in a single-dose toxicology study in dogs. QTc prolongation occurred at or below the human exposure at the maximum human induction dose.”
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 Cypsedo 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: Target organs: CNS and cardiovascular system (FDA multi-discipline review, p. 39)
NOAEL / key findings
Target organs: CNS and cardiovascular system
“Target organs of toxicity identified after cipepofol administration were the central nervous system and cardiovascular system.”
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
Extensive distribution in rats, highest in adrenal, fat, skin, ovary, pancreas and kidney; crosses blood-brain barrier
“Following IV administration of cipepofol injectable emulsion, extensive tissue distribution was observed in Sprague-Dawley rats, with the highest exposures found in the adrenal gland, fat, skin, ovary, pancreas, and kidney. Cipepofol was demonstrated to cross the blood-brain barrier.”
Modality-specific risk
Exaggerated pharmacology (respiratory depression, anesthesia-related mortality) and QTc prolongation
“Several adverse findings were identified from the nonclinical studies but were generally attributed to the pharmacological effects of the active pharmaceutical ingredient (e.g., muscle relaxation, respiratory depression, anesthesia related mortality) or can be clinically monitored (e.g., QTc prolongation, local irritation).”
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.
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 Cypsedo 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: Target organs: CNS and cardiovascular system (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day rat and dog IV studies, dosing every other day; recovery phase not stated
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
Pivotal GLP studies
28-day rat and dog studies with every-other-day dosing (plus 14-day studies)
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development); rat (pre- and postnatal)
“In the embryo-fetal developmental studies, cipepofol was not detected in the plasma of fetal rats or rabbits on Gestation Day 20 or Gestation Day 29, respectively. In the pre- and postnatal toxicity study, the test article was detected in milk samples from F0 females.”
Reproductive & developmental
Rat FEED: increased post-implantation loss from resorptions, likely related to maternal hypoxia secondary to anesthesia
“It appears that the significantly increased post-implantation loss was mainly driven by increased resorption. Similar, but not significant and not dose-dependent, effects were observed in the FEED study in rats with every other day IV dosing. The reproductive effects observed in the FEED studies are likely related to maternal hypoxia secondary to anesthesia.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the prenatal and postnatal development (PPND) study in rats, there were no test article-related adverse effects observed on parturition and lactation of F0 females;”
Carcinogenicity
Species: carcinogenicity
Not conducted (not required for acute use)
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
Carcinogenicity model
Not conducted (acute-use indication)
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
Carcinogenicity timing
Not required for an acute-use product
“Carcinogenicity studies are not required to approve a drug product indicated for acute use.”
Safety marginopen answer page →
Safety margin at NOAEL
At least 1x human AUC margin in 14- or 28-day rat/dog repeat-dose studies
“At least 1 x exposure margin was achieved in either the 14-day or 28- day repeat-dose studies in dogs or rats.”
NOAEL / key findings
Target organs: CNS and cardiovascular system
“Target organs of toxicity identified after cipepofol administration were the central nervous system and cardiovascular system.”
Efficacy evidenceopen answer page →
Efficacy evidence
Anesthesia in normal rats, dogs and minipigs, similar depth to propofol with 6-fold higher potency
“In animal studies, including rats, dogs, and minipigs, cipepofol produced anesthesia at a similar depth as propofol, but with a 6-fold higher anesthetic potency.”
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
Mechanism not first in class, minimal off-target activity; prior GABAA agonist experience informs risk
“Although the drug product is a new molecular entity, the mechanism of action is not first in class and off-target activity is minimal. There is significant amount of knowledge from clinical experience regarding potential adverse effects associated with other GABAA receptor agonists.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile rat toxicity and neonatal neurotoxicity studies deferred to postmarketing requirements
Why: Needed only before clinical studies in pediatric patients from birth to under 3 years · Other reason
“Conduct a juvenile animal study in rats to support the initiation of clinical studies in pediatric patients from birth to less than 3 years of age.”
“From a nonclinical pharmacology toxicology perspective, NDA 220482 may be approved with Pediatric Research Equity Act (PREA) postmarketing requirements.”
Impurity or metaboliteAccepted
No safety characterization of the major human O-glucuronide metabolite M4, poorly covered in rats
Why: Non-acyl glucuronide conjugate, pharmacologically inactive · Within the guideline · Pharmacology or kinetics
“M4 is a non-acyl-glucuronic acid metabolite confirmed by the CMC Reviewer and demonstrated to not be pharmacologically active. No additional safety characterization was conducted for M4, which was deemed acceptable by the Division during drug development.”
OtherAcceptedBeyond the letter
Repeat-dose general toxicology studies dosed every other day rather than daily
“The Division acknowledged the Applicant’s justification for dosing animals every other day in the repeat-dose general toxicology studies.”
OtherCriticised but acceptedBeyond the letter
Local tolerance histopathology done on Day 3 or 4 after dosing; no acute local assessment
Why: Clinical data can be leveraged for the local safety assessment · Human data
“Note that the assessment of histopathology was conducted on Day 3 or Day 4 after the final dose; therefore, the acute assessment of the local effects was not adequate, although clinical observation on the dosing site was conducted at several more acute time points after dosing.”
“The lack of acute local histopathological assessment of the dosing site is not considered an approval issue, given that clinical data can be leveraged for the local safety assessment.”
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