Quviviq
daridorexant
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
“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”
Why that species
Orexin receptor binding with high potency, human-like metabolic pathways and partly similar plasma protein binding
“Species selection was based on pharmacologically relevant binding to Orexin receptors in humans and in these non-clinical species with high selectivity and potency, metabolically relevant pathways in these species are similar to those in humans, as well as close plasma protein binding properties for some species only.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In Beagle dogs were administered 10, 30, or 100mg/kg/day Daridorexant for 39 consecutive weeks”
Species: general tox
Rat (26-week) and dog (39-week); mouse up to 28 days
“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”
Species: DART
Rat and rabbit (embryo-fetal development); rat (pre/postnatal development)
“In animal reproduction studies, oral administration of daridorexant to pregnant rats and rabbits during the period of organogenesis did not cause fetal toxicity or malformation at doses up to 8 and 10 times the maximum recommended human dose (MRHD) of 50 mg, respectively, based on AUC.”
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Surrogate used in
No surrogate used; daridorexant tested directly in pharmacologically relevant rats and dogs
“Rats and dogs are pharmacologically species relevant for daridorexant, as the orexin system is highly conserved across mammalian species, and as activity on sleep parameters had been clearly demonstrated.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies, each with 8-week recovery
“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”
Route in tox
Oral (gavage)
“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and in vivo rat micronucleus assays
“Daridorexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mammalian chromosome aberration assay in human lymphocytes and was not clastogenic in the in vivo rat micronucleus assay.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Reproductive & developmental
Rat and rabbit EFD: no effects on embryo-fetal survival and no malformations
“Embryo-fetal development toxicity studies were conducted in rats and rabbits. Treatment-related effects on embryo-foetal survival or foetal malformations were not reported in any species.”
Safety pharmacology
Weak hERG inhibition (IC50 25 µM); no adverse CNS, cardiovascular or respiratory effects at relevant levels
“In an in vitro hERG assay (Study T-14.012, GLP), daridorexant induced weak inhibition of the potassium current with an IC20 of 7.4µM (~3400 ng/mL) and IC50 of 25µM (~11500 ng/mL), respectively.”
Genotox: Ames
Negative (not mutagenic in Ames assay)
“Daridorexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay”
Genotox: in vitro mammalian
Chromosome aberration assay in human lymphocytes: negative
“Daridorexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mammalian chromosome aberration assay in human lymphocytes”
Genotox: in vivo
Rat micronucleus assay: negative (not clastogenic)
“was not clastogenic in the in vivo rat micronucleus assay.”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no increase in tumors
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Carcinogenicity timing
2-year rat and 6-month Tg.rasH2 mouse completed before the marketing application
“2-year and 6-month carcinogenicity studies in the rat and Tg.rasH2 mouse, respectively”
hERG / QT
Weak hERG inhibition (IC20 7.4 µM, IC50 25 µM)
“In an in vitro hERG assay (Study T-14.012, GLP), daridorexant induced weak inhibition of the potassium current with an IC20 of 7.4µM (~3400 ng/mL) and IC50 of 25µM (~11500 ng/mL), respectively.”
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 Quviviq 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: 39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes (FDA integrated review, p. 179)
NOAEL / key findings
39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes
“Based on the cataplexy-like clinical signs and increased liver enzyme levels, the NOAEL is considered to be 10 mg/kg/day in both males and females in the 39-week dog study.”
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
Rat QWBA: no accumulation in uveal tract, pigmented skin or meninges; no melanin binding
“There was no significant distribution/accumulation of radioactivity in the uveal tract/retina, pigmented skin, or meninges of the brain, suggesting that daridorexant does not bind to melanin.”
Modality-specific risk
Cataplexy-like signs in dogs from exaggerated orexin receptor antagonism
“The cataplexy-like effects at higher doses in the dog are due to the exaggerated pharmacology of orexin receptor antagonists.”
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.
Label warnings
- CNS-Depressant Effects and Daytime Impairment
- Worsening of Depression/Suicidal Ideation
- Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms
- Complex Sleep Behaviors
- Patients with Compromised Respiratory Function
- Need to Evaluate for Co-morbid Diagnoses
PsychiatricPulmonary toxicity
US prescribing information, 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 Quviviq 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: 39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes (FDA integrated review, p. 179)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral gavage) with 8-week treatment-free period
“Daridorexant - 39-Week Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies, each with 8-week recovery
“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”
DART package
Species: DART
Rat and rabbit (embryo-fetal development); rat (pre/postnatal development)
“In animal reproduction studies, oral administration of daridorexant to pregnant rats and rabbits during the period of organogenesis did not cause fetal toxicity or malformation at doses up to 8 and 10 times the maximum recommended human dose (MRHD) of 50 mg, respectively, based on AUC.”
Reproductive & developmental
Rat and rabbit EFD: no effects on embryo-fetal survival and no malformations
“Embryo-fetal development toxicity studies were conducted in rats and rabbits. Treatment-related effects on embryo-foetal survival or foetal malformations were not reported in any species.”
PPND / ePPND: when
PPND in rat completed before the marketing application; no maternal or developmental toxicity
“Daridorexant was administered orally to pregnant rats during gestation and lactation at doses of 50, 100, and 300 mg/kg/day, which are approximately 1, 3, and 9 times the MRHD of 50 mg, respectively, based on AUC.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no increase in tumors
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Carcinogenicity timing
2-year rat and 6-month Tg.rasH2 mouse completed before the marketing application
“2-year and 6-month carcinogenicity studies in the rat and Tg.rasH2 mouse, respectively”
Safety marginopen answer page →
Safety margin at NOAEL
39-week dog NOAEL ~1.5x human exposure at MRHD 50 mg (Cmax and AUC)
“which provided a safety margin of ~1.5 -fold relative to the proposed MRHD of 50 mg, based on both Cmax and AUC.”
NOAEL / key findings
39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes
“Based on the cataplexy-like clinical signs and increased liver enzyme levels, the NOAEL is considered to be 10 mg/kg/day in both males and females in the 39-week dog study.”
Efficacy evidenceopen answer page →
Efficacy evidence
Sleep-wake EEG studies in naive rats and dogs (decreased wake, increased REM/non-REM sleep); no disease model
“Proof-of-concept for the indication was sufficiently demonstrated in in vivo primary pharmacology studies using as usually naive rats and dogs as models.”
Why that model
Orexin system highly conserved across mammals, so sleep effects measurable directly in normal rats and dogs
“Rats and dogs are pharmacologically species relevant for daridorexant, as the orexin system is highly conserved across mammalian species, and as activity on sleep parameters had been clearly demonstrated.”
Reviewer's view of the efficacy data
EMA: proof-of-concept sufficiently demonstrated in in vivo pharmacology studies in naive rats and dogs
“Proof-of-concept for the indication was sufficiently demonstrated in in vivo primary pharmacology studies using as usually naive rats and dogs as models.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
Tg.rasH2 mouse high dose gave only 4.37- to 8.5-fold AUC multiples, below the 50-fold ICH S1 criterion
Why: Possible limiting toxicity over 26 weeks, based on liver necrosis at 1500 mg/kg/day in the 4-week dose-range-finding study · Other reason
“Selection of high dose for carcinogenicity study should be 50-fold ratio (AUC) in TgrasH2 mice according to ICHS1, however the multiple of exposure ratio for the 1000 mg/kg high dose are only 8.5-4.37 fold (males-females) for Daridorexant, and comprised between 5.3 and 7.7 fold for metabolites.”
“This high dose may be accepted considering possible limiting toxicity for a 26-week treatment duration based on liver necrosis from the 4 week-DRF study at 1500 mg/kg/day.”
DARTCriticised but acceptedBeyond the letter
Pre/postnatal rat study high dose set at 300 mg/kg/day although 450 mg/kg/day could have been tested
Why: Maternal deaths and cataplexy-like clinical signs at higher doses in other studies · Other reason
“Based on the maternal death and cataplexy-like clinical signs, 300 mg/kg/day was selected as the high dose for the current study, which is acceptable, although 450 mg/kg/day could have been selected and tested as the high dose.”
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