Simtriyo
centanafadine
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
43 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
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 repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 43 weeks)
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”
Species: carcinogenicity
Transgenic mouse (6-month) and rat (2-year)
“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Surrogate used in
No surrogate used; centanafadine tested directly in rats and dogs
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
Study lengthopen answer page →
Longest pivotal study
43 (43-week juvenile dog)
“Dog, juvenile 43-week (GLP)”
Pivotal GLP studies
Oral repeat-dose studies up to 26 weeks in rats and 43 weeks in dogs
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
Route in tox
Oral
“• Oral doses: 0, 3 (LD), 10 (MD), or 30 (HD) mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, CHO chromosome aberration and rat in vivo micronucleus assays
“Centanafadine was negative in a valid, full battery of genetic toxicology assays including a reverse bacterial mutagenicity (Ames) assay, a chromosome aberration assay (CHO cells), and a rat in vivo micronucleus assay.”
Carcinogenicity
6-month transgenic mouse and 2-year rat: no drug-related neoplasms
“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. There was no evidence of drug-related neoplasms in either study.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND and rat juvenile studies conducted
“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”
Safety pharmacology
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.
Genotox: Ames
Negative
“Centanafadine was negative in a valid, full battery of genetic toxicology assays including a reverse bacterial mutagenicity (Ames) assay, a chromosome aberration assay (CHO cells), and a rat in vivo micronucleus assay.”
Genotox: in vitro mammalian
Negative chromosome aberration assay in CHO cells
“Centanafadine was negative in a valid, full battery of genetic toxicology assays including a reverse bacterial mutagenicity (Ames) assay, a chromosome aberration assay (CHO cells), and a rat in vivo micronucleus assay.”
Genotox: in vivo
Negative rat in vivo micronucleus assay
“Centanafadine was negative in a valid, full battery of genetic toxicology assays including a reverse bacterial mutagenicity (Ames) assay, a chromosome aberration assay (CHO cells), and a rat in vivo micronucleus assay.”
Carcinogenicity model
6-month transgenic mouse and 2-year rat; no drug-related neoplasms
“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. There was no evidence of drug-related neoplasms in either study.”
Carcinogenicity timing
Rat and mouse carcinogenicity studies completed and submitted with the NDA
“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Simtriyo 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-limiting but monitorable body weight reductions; no unmonitorable toxicities below body-weight-effect doses (FDA multi-discipline review, p. 35)
NOAEL / key findings
Dose-limiting but monitorable body weight reductions; no unmonitorable toxicities below body-weight-effect doses
“The reductions in body weight were dose-limiting in animals and would be monitorable in humans. There were no unmonitorable toxicities observed at doses below those with adverse effects on body weight.”
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
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.
Modality-specific risk
Abuse potential (CNS stimulant); recommended for Schedule III
“CSS reviewed the nonclinical and clinical abuse-related data submitted in NDA 218145 for centanafadine and concluded that the drug has abuse potential and should be recommended for placement in Schedule III of the CSA, if the NDA for centanafadine is approved as a drug product.”
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 Simtriyo 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-limiting but monitorable body weight reductions; no unmonitorable toxicities below body-weight-effect doses (FDA multi-discipline review, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
43-week dog study (longest); recovery phase included, length not given
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
Pivotal GLP studies
Oral repeat-dose studies up to 26 weeks in rats and 43 weeks in dogs
“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”
DART package
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND and rat juvenile studies conducted
“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”
PPND / ePPND: when
PPND in rat completed and submitted with the marketing application
“Reproductive and developmental toxicity studies that were conducted included fertility studies in male and female rats, embryofetal development (EFD) studies in rats and rabbits, a pre- and post-natal development (PPND) study in rats, and a juvenile animal study (JAS) in rats.”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (6-month) and rat (2-year)
“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study.”
Carcinogenicity model
6-month transgenic mouse and 2-year rat; no drug-related neoplasms
“Centanafadine was adequately evaluated in a 6-month transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. There was no evidence of drug-related neoplasms in either study.”
Carcinogenicity timing
Rat and mouse carcinogenicity studies completed and submitted with the NDA
“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat NOAEL: male AUC ~0.1x, female ~0.8x human AUC at MRHD
“At the NOAEL, male AUC is lower than (~0.1x), and female AUC is approximately equal to (~0.8x), human AUC at the MRHD.”
NOAEL / key findings
Dose-limiting but monitorable body weight reductions; no unmonitorable toxicities below body-weight-effect doses
“The reductions in body weight were dose-limiting in animals and would be monitorable in humans. There were no unmonitorable toxicities observed at doses below those with adverse effects on body weight.”
Efficacy evidenceopen answer page →
Efficacy evidence
Microdialysis in normal rats: increased cortical NE, DA and 5-HT
“Oral centanafadine dose-dependently increased NE, DA, and 5-HT levels in the prefrontal cortex as well as DA and 5-HT levels in the ventral striatum.”
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
FDA: microdialysis data cannot establish the relative importance of serotonin transporter activity
“Although the effect of centanafadine on percent change relative to baseline was larger for 5-HT than NE or DA, we cannot infer the relative importance of serotonin transporter activity from this data because the basal levels of 5-HT were approximately 20-fold lower than NE or DA and the effects on post-synaptic neurons were not measured.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
26-week rat NOAEL exposure below human AUC at the MRHD (~0.1x males, ~0.8x females)
Why: Dose-limiting body weight reductions would be monitorable in humans; no unmonitorable toxicities below those doses · Other reason
“At the NOAEL, male AUC is lower than (~0.1x), and female AUC is approximately equal to (~0.8x), human AUC at the MRHD.”
“The reductions in body weight were dose-limiting in animals and would be monitorable in humans. There were no unmonitorable toxicities observed at doses below those with adverse effects on body weight.”
Safety marginVerdict not stated
Rat embryofetal NOAEL for maternal toxicity and fetal development below human exposure at the MRHD
“The No Observed Adverse Effect Level (NOAEL) for both maternal toxicity and fetal development was 10 mg/kg/day, which is below the human exposure at the MRHD based on AUC.”
Impurity or metaboliteAcceptedBeyond the letter
Enantiomer impurity EB-1070 specified above the ICH Q3A(R2) qualification threshold
Why: Qualified by the submitted toxicology data · Weight of evidence
“The Applicant’s drug specification proposed a limit for the enantiomer impurity (EB-1070) which was above the qualification threshold recommended in the ICH Q3A(R2)1 guidance. Based on the toxicology data submitted by the Applicant, the proposed limit for the EB-1070 impurity is considered qualified.”
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