Orzeyful
oveporexton
Sources:FDA multi-discipline review ↗
Species
MonkeyRat
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 cynomolgus monkey
“Single-dose and repeat-dose general toxicity studies were performed in Sprague-Dawley rats (up to 26-weeks duration) and in cynomolgus monkeys (up to 39-weeks duration). In rats, the primary target organs of toxicity included incisors, kidneys, and liver.”
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
“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”
Species: general tox
Sprague-Dawley rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“Single-dose and repeat-dose general toxicity studies were performed in Sprague-Dawley rats (up to 26-weeks duration) and in cynomolgus monkeys (up to 39-weeks duration).”
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal development (EFD) studies in pregnant rats and rabbits, maternal toxicity (decreases in body weight and body weight gain) was noted in both species at the highest doses tested (750 mg/kg/day and 100 mg/kg/day, in rats and rabbits respectively).”
Species: carcinogenicity
Rat (2-year) and Tg-rasH2 mouse (26-week)
“Refer to section 5.5.4 for a summary of the negative GLP-compliant carcinogenicity studies of oveporexton: a 26-week carcinogenicity study in transgenic hemizygous mice (Tg-rasH2 mice) and a 2-year carcinogenicity study in rats.”
Surrogate used in
No surrogate used; oveporexton itself tested in rats and monkeys
“Single-dose and repeat-dose general toxicity studies were performed in Sprague-Dawley rats (up to 26-weeks duration) and in cynomolgus monkeys (up to 39-weeks duration).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey repeat-dose studies
“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”
Route in tox
Oral gavage
“Route of administration: Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo micronucleus; positive in vitro micronucleus (24-hour); overall non-genotoxic
“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment. Overall oveporexton was determined to be non-genotoxic.”
Carcinogenicity
2-year rat and 6-month transgenic mouse: not carcinogenic
“Oveporexton was also found to be non-carcinogenic in a GLP 2-year rat and a GLP 6-month transgenic mouse carcinogenicity study.”
Reproductive & developmental
Rat and rabbit EFD: no drug-related malformations or embryo-fetal lethality
“There were no drug-related effects on the incidence of congenital malformations or embryo-fetal lethality in either rats or rabbits.”
Safety pharmacology
Rats: CNS (body temperature changes, hyperactivity at ≥20 mg/kg) and respiratory effects; monkeys: increased blood pressure and LV pressure at ≥3 mg/kg
“Results from GLP-compliant safety pharmacology studies indicated that oveporexton can affect the CNS (increased body temperature at 20 and 100 mg/kg, decreased body temperature at 1000 mg/kg, and hyperactivity at ≥20 mg/kg in rats), the cardiovascular system (increased blood pressure and left ventricular pressure at ≥3 mg/kg in monkeys), and the respiratory system”
Genotox: Ames
Negative
“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment.”
Genotox: in vitro mammalian
In vitro micronucleus: positive after 24-hour continuous treatment; overall judged non-genotoxic
“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment. Overall oveporexton was determined to be non-genotoxic.”
Genotox: in vivo
In vivo micronucleus: negative
“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment.”
Carcinogenicity model
2-year rat; 26-week Tg-rasH2 mouse; both negative
“Refer to section 5.5.4 for a summary of the negative GLP-compliant carcinogenicity studies of oveporexton: a 26-week carcinogenicity study in transgenic hemizygous mice (Tg-rasH2 mice) and a 2-year carcinogenicity study in rats.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse carcinogenicity studies completed and reviewed with the NDA
“Oveporexton was also found to be non-carcinogenic in a GLP 2-year rat and a GLP 6-month transgenic mouse carcinogenicity study.”
hERG / QT
hERG IC50 >3 µg/mL, >3000-fold human unbound Cmax at MRHD
“The IC50 value for hERG inhibition was >3 μg/mL, which provides an approximate safety margin of >3000-fold compared with the human Cmax,ss,unbound (0.98 ng/mL) at the MRHD (Study No.B240294).”
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 Orzeyful 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: 26-week rat NOAEL 100 mg/kg in both sexes (FDA multi-discipline review, p. 68)
NOAEL / key findings
26-week rat NOAEL 100 mg/kg in both sexes
“• NOAEL: 100 mg/kg for both sexes, associated with a mean Cmax of 7860 and 11,800 ng/mL, and a mean AUC24h of 115,000 and 168,000 h*ng/mL in males and females, respectively, in Week 26 of dosing.”
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
No melanin binding; placental transfer to fetus and secretion into milk in rats
“liver, with no evidence of binding to melanin-containing tissues. Oveporexton can be transferred into the fetus via the placenta during gestation and is also secreted into milk in lactating rats.”
Modality-specific risk
Tooth fluorosis from increased fluoride, considered a rodent-specific metabolism-related change
“This finding was indicative of tooth fluorosis caused by increased fluoride concentrations which disrupts enamel formation. The tooth fluorosis is considered a species-specific metabolism-related change for rodents.”
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 Orzeyful 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: 26-week rat NOAEL 100 mg/kg in both sexes (FDA multi-discipline review, p. 68)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey oral gavage GLP study; recovery phase not stated
“Study Title/Number: 39-Week Oral Gavage Toxicity Study of TAK-861 in Monkeys/B-8934”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey repeat-dose studies
“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal development (EFD) studies in pregnant rats and rabbits, maternal toxicity (decreases in body weight and body weight gain) was noted in both species at the highest doses tested (750 mg/kg/day and 100 mg/kg/day, in rats and rabbits respectively).”
Reproductive & developmental
Rat and rabbit EFD: no drug-related malformations or embryo-fetal lethality
“There were no drug-related effects on the incidence of congenital malformations or embryo-fetal lethality in either rats or rabbits.”
PPND / ePPND: when
PPND in rat completed and reviewed with the NDA; no drug-related effects
“In the pre- and postnatal development (PPND) study in rats, there were no drug-related effects on maternal endpoints or reproductive function, or on offspring development (survival, growth, behavior, and reproductive function).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg-rasH2 mouse (26-week)
“Refer to section 5.5.4 for a summary of the negative GLP-compliant carcinogenicity studies of oveporexton: a 26-week carcinogenicity study in transgenic hemizygous mice (Tg-rasH2 mice) and a 2-year carcinogenicity study in rats.”
Carcinogenicity model
2-year rat; 26-week Tg-rasH2 mouse; both negative
“Refer to section 5.5.4 for a summary of the negative GLP-compliant carcinogenicity studies of oveporexton: a 26-week carcinogenicity study in transgenic hemizygous mice (Tg-rasH2 mice) and a 2-year carcinogenicity study in rats.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse carcinogenicity studies completed and reviewed with the NDA
“Oveporexton was also found to be non-carcinogenic in a GLP 2-year rat and a GLP 6-month transgenic mouse carcinogenicity study.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week NOAEL ~311x (males) and 455x (females) human AUC at MRHD
“Safety margins at the NOAEL compared to the MRHD are approximately 311- and 455-fold for males and females, respectively based on AUC.”
NOAEL / key findings
26-week rat NOAEL 100 mg/kg in both sexes
“• NOAEL: 100 mg/kg for both sexes, associated with a mean Cmax of 7860 and 11,800 ng/mL, and a mean AUC24h of 115,000 and 168,000 h*ng/mL in males and females, respectively, in Week 26 of dosing.”
Efficacy evidenceopen answer page →
Efficacy evidence
OX/ataxin-3 transgenic NT1 mouse model (loss of orexin neurons): increased wakefulness
“The effect of oveporexton on wakefulness during the sleep phase was also demonstrated in OX/ataxin-3 transgenic mice (a NT1 mouse model in which the transgene selectively eliminates orexin producing neurons in the hypothalamus) and their non-transgenic WT littermates.”
Why that model
Monkeys added because mice are nocturnal; diurnal monkeys have a sleep/wake structure closer to humans
“Because mice are nocturnal animals with a polyphasic sleep/wake structure, studies were also conducted in cynomolgus monkeys which are diurnal and have a monophasic sleep/wake structure more analogous to humans.”
Reviewer's view of the efficacy data
FDA: OX2R-selective agonist that produced wakefulness and ameliorated narcolepsy-like features in relevant animal models
“Overall, the primary pharmacology studies demonstrated that oveporexton acts as a OX2R agonist, with much greater selectively for OX2R versus OXR1, and is capable of producing wakefulness and ameliorating narcolepsy-like characteristics in relevant animal models.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Positive in vitro micronucleus assay after continuous treatment; overall judged non-genotoxic on negative Ames and in vivo micronucleus
Why: Negative Ames and in vivo micronucleus assays · Weight of evidence
“Oveporexton was found to be negative in an Ames assay and in an in vivo micronucleus assay; however, it was found to be positive for induction of micronuclei in an in vitro micronucleus assay following 24-hours of continuous treatment. Overall oveporexton was determined to be non-genotoxic.”
“The overall weight of evidence indicates that TAK-861 has no genotoxic potential.”
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