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.”
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.”
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.”