Qulipta
atogepant
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 rhesus monkey
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
Why that species
ADME data in rat and rhesus monkey support their use
“The ADME data submitted for rat and rhesus monkey provide supporting evidence for the use of these species in the atogepant toxicity studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
Species: general tox
Rat (6-month) and monkey (9-month)
“A complete nonclinical package was submitted to the NDA, which included general toxicology studies of up to 6 and 9 months’ duration in rat and monkey, respectively;”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“2-year carcinogenicity studies in mouse and rat; and reproductive and development studies (fertility and early embryonic, embryofetal development, and pre- and postnatal development studies in rat; embryofetal development study in rabbit).”
Species: carcinogenicity
Mouse and rat (2-year)
“2-year carcinogenicity studies in mouse and rat; and reproductive and development studies (fertility and early embryonic, embryofetal development, and pre- and postnatal development studies in rat; embryofetal development study in rabbit).”
Surrogate used in
No surrogate used; atogepant tested directly in rats and monkeys
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“In the pivotal 9-month oral toxicology study in monkey (4/sex/group, 0, 15, 40, or 300 mg/kg) there were no drug-related findings.”
Pivotal GLP studies
6-month rat and 9-month rhesus monkey oral studies
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
Route in tox
Oral
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat bone marrow micronucleus assays
“Atogepant was negative in Organisation for Economic Cooperation and Development-compliant Ames, in vitro chromosomal aberration, and in vivo rat bone marrow micronucleus assays.”
Carcinogenicity
2-year mouse and rat: not carcinogenic; female mouse high dose not adequately justified
“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic. The study in female mice was not adequate because the HD was not adequately justified”
Reproductive & developmental
Rat and rabbit EFD: embryolethality, lower fetal weight (rats) and fetal variations above clinical exposures
“In animal studies, oral administration of atogepant during organogenesis resulted in embryolethality, adverse effects on embryofetal development (decreased fetal body weight in rats, increased incidences of fetal variations in rats and rabbits) at maternal exposures greater those used clinically.”
Safety pharmacology
No concerns in CNS, cardiovascular and respiratory safety pharmacology
“A complete battery of safety pharmacology (CNS, cardiovascular, and respiratory) endpoints was adequately assessed and showed no safety concerns.”
Genotox: Ames
Negative
“Atogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration test in CHO cells: negative
“Atogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Atogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.”
Carcinogenicity model
2-year mouse and 2-year rat: not carcinogenic; female mouse high dose not adequately justified
“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic. The study in female mice was not adequate because the HD was not adequately justified;”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed and reviewed in the NDA
“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic.”
hERG / QT
Weak hERG inhibition (23.9% at 28 µM); unlikely to affect repolarisation at clinical doses
“atogepant exhibited weak hERG current inhibition (23.9% inhibition at 28 µM), which suggests that atogepant is unlikely to alter ventricular repolarisation in humans at clinically effective doses.”
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 Qulipta 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: 6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD) (EMA assessment report, p. 23)
NOAEL / key findings
6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD)
“The applicant considers that the NOAEL for atogepant in rats was 100 mg/kg/day in the 6-month study with an AUC0-24hr of 192.5 µM•hr, which represents an approximately 33-fold margin over the clinical exposure of about 5.75 µM•hr following 60 mg QD dosing.”
Risksopen answer page →
Immune & cytokine safety
ICH S8 weight-of-evidence review raised no immunotoxicity concerns
“The applicant has provided a weight of evidence review in accordance with ICH S8 which did not reveal any concerns.”
Biodistribution & persistence
Wide distribution in rats; negligible levels in CNS, eye and bone
“Most tissues had concentrations similar to those in blood, except for central nervous system tissues, eye and bone, which had negligible concentrations.”
Modality-specific risk
Class hepatotoxicity: DILIsym modelling predicted lower ALT-elevation risk than discontinued gepants
“Results of the “DILIsym” modeling suggest that atogepant has a reduced risk of causing clinically relevant elevations of ALT in excess of 3-fold the upper limit of normal (≥ 3X ULN) compared to telcagepant and MK-3207.”
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
- Hypersensitivity Reactions
- 2 Hyper tension
- 3 Raynaud’s Phenomenon
Hypersensitivity & infusion reactionsCardiovascular
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 Qulipta 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: 6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD) (EMA assessment report, p. 23)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month GLP rhesus monkey oral study with 3-month interim necropsy; no recovery phase stated
“Study TT #13-1074: Nine-Month Oral Toxicity Study in Rhesus Monkeys with a Three-Month Interim Necropsy”
Pivotal GLP studies
6-month rat and 9-month rhesus monkey oral studies
“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“2-year carcinogenicity studies in mouse and rat; and reproductive and development studies (fertility and early embryonic, embryofetal development, and pre- and postnatal development studies in rat; embryofetal development study in rabbit).”
Reproductive & developmental
Rat and rabbit EFD: embryolethality, lower fetal weight (rats) and fetal variations above clinical exposures
“In animal studies, oral administration of atogepant during organogenesis resulted in embryolethality, adverse effects on embryofetal development (decreased fetal body weight in rats, increased incidences of fetal variations in rats and rabbits) at maternal exposures greater those used clinically.”
PPND / ePPND: when
GLP rat PPND completed and included in the marketing application
“In the GLP pre- and postnatal developmental toxicity study in rats, atogepant was administered at dose levels of 0 (vehicle), 15, 45 or 125 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“2-year carcinogenicity studies in mouse and rat; and reproductive and development studies (fertility and early embryonic, embryofetal development, and pre- and postnatal development studies in rat; embryofetal development study in rabbit).”
Carcinogenicity model
2-year mouse and 2-year rat: not carcinogenic; female mouse high dose not adequately justified
“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic. The study in female mice was not adequate because the HD was not adequately justified;”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed and reviewed in the NDA
“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month monkey NOAEL (300 mg/kg) 10-fold human AUC at MRHD
“At the HD (300 mg/kg) in the 9-month study, the safety margin was 10-fold compared to that at the MRHD based on plasma AUC at the NOAEL.”
NOAEL / key findings
6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD)
“The applicant considers that the NOAEL for atogepant in rats was 100 mg/kg/day in the 6-month study with an AUC0-24hr of 192.5 µM•hr, which represents an approximately 33-fold margin over the clinical exposure of about 5.75 µM•hr following 60 mg QD dosing.”
Efficacy evidenceopen answer page →
Efficacy evidence
Capsaicin-induced dermal vasodilatation (CIDV) inhibition as surrogate pharmacodynamic marker; no animal migraine model
“A specific animal model for the evaluation of prophylactic effects of atogepant on migraine was not provided by the applicant. As a surrogate pharmacological parameter for clinical efficacy of atogepant in the prophylaxis of migraine, inhibition of capsaicin-induced dermal vasodilatation (CIDV), an effect considered to be mediated largely by release of CGRP, was used by the applicant.”
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
EMA: precise mechanism of atogepant in migraine prophylaxis remains to be established
“However, the precise mechanism of atogepant in the prophylaxis of migraine remains to be established.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Female mouse carcinogenicity study inadequate: high dose not an MTD or MFD and below 25-fold human exposure
Why: Dose range-finding study, and a repeat female mouse study if needed, may be conducted postmarketing
“The study in female mice was not adequate because the HD was not adequately justified; it was not demonstrated to be a maximum tolerated dose or maximum feasible dose and did not achieve plasma exposures at least 25-fold that at in humans at the MRHD.”
“If the HD is determined not to be adequate, the carcinogenicity study will need to be repeated in female mice with an adequate HD. These may be conducted as postmarketing requirements.”
Efficacy modelVerdict not stated
No animal model of migraine prevention; inhibition of capsaicin-induced dermal vasodilatation used as surrogate pharmacodynamic marker
“A specific animal model for the evaluation of prophylactic effects of atogepant on migraine was not provided by the applicant. As a surrogate pharmacological parameter for clinical efficacy of atogepant, inhibition of capsaicin-induced dermal vasodilatation (CIDV), an effect considered to be mediated largely by release of CGRP, was used by the applicant.”
DARTVerdict not stated
Rat fertility study without toxicokinetics; margins calculated from the embryo-fetal development study
Why: Exposure data from the rat embryo-fetal development study used instead
“No toxicokinetic data were collected. (The exposure data from the rat embryofetal development study was used to calculate margins.)”
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