Ubrelvy
ubrogepant
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
“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”
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
“The general toxicity of orally administered ubrogepant was assessed in CD-1 mouse (3-month), Wistar rat (7- and 14-day, 1-, 3-, and 6-month), and rhesus monkey (3- and 9-month) GLP-compliant studies.”
Species: general tox
Rat (6-month) and rhesus monkey (9-month)
“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”
Species: DART
Wistar rat (fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“A standard battery of reproductive and development toxicology studies was conducted for ubrogepant: fertility and early embryonic development (0, 20, 80, and 160 mg/kg), embryofetal development (0, 1.5, 5. 25, and 125 mg/kg), and pre- and postnatal development (0, 25, 60, and 160 mg/kg) in Wistar rat, and an embryofetal development in New Zealand White rabbit”
Species: carcinogenicity
CD-1 mouse and Wistar rat (104-week oral)
“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”
Surrogate used in
No surrogate used; ubrogepant tested directly in mouse, rat and rhesus monkey
“The general toxicity of orally administered ubrogepant was assessed in CD-1 mouse (3-month), Wistar rat (7- and 14-day, 1-, 3-, and 6-month), and rhesus monkey (3- and 9-month) GLP-compliant studies.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”
Pivotal GLP studies
6-month rat and 9-month rhesus monkey oral studies
“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”
Route in tox
Oral
“Ubrogepant was administered orally in all toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat bone marrow micronucleus assays
“In genetic toxicology assessments, ubrogepant was negative in OECD-compliant Ames, in vitro chromosomal aberration, and in vivo rat bone marrow micronucleus assays.”
Carcinogenicity
104-week CD-1 mouse and Wistar rat oral studies: no drug-related neoplasms
“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”
Reproductive & developmental
Rabbit EFD: embryofetal mortality; rat PPND: lower offspring body weight; both at maternally toxic doses
“In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at doses greater than those used clinically and which were associated with maternal toxicity”
Safety pharmacology
hERG negative; no respiratory (75 mg/kg) or cardiovascular (300 mg/kg) effects in telemetered rhesus monkeys
“Ubrogepant was negative in an in vitro hERG assay. There were no effects on respiratory or cardiovascular parameters at oral doses up to 75 mg/kg or 300 mg/kg, respectively, in telemetered Rhesus monkeys.”
Genotox: Ames
Negative
“In genetic toxicology assessments, ubrogepant was negative in OECD-compliant Ames, in vitro chromosomal aberration, and in vivo rat bone marrow micronucleus assays.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster ovary cells: negative
“Ubrogepant 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
“Ubrogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.”
Carcinogenicity model
104-week oral CD-1 mouse and Wistar rat; mouse study judged inadequate (AUC margin <25-fold MRHD)
“Ubrogepant was negative in 104-week mouse (up to 50 mg/kg) and rat (up to 100(M) and 150(F)) carcinogenicity studies, according to the FDA statistical analysis. However, the mouse study was not adequate because the safety margin based on AUC at the highest dose tested was less than 25-fold the MRHD.”
Carcinogenicity timing
104-week CD-1 mouse and Wistar rat studies completed before the marketing application
“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”
hERG / QT
Negative in hERG assay; no cardiovascular effects up to 300 mg/kg in telemetered rhesus monkeys
“Ubrogepant was negative in an in vitro hERG assay. There were no effects on respiratory or cardiovascular parameters at oral doses up to 75 mg/kg or 300 mg/kg, respectively, in telemetered Rhesus monkeys.”
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 Ubrelvy 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: No adverse findings up to 160 mg/kg (6-month rat) and 175 mg/kg (9-month monkey) (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
No adverse findings up to 160 mg/kg (6-month rat) and 175 mg/kg (9-month monkey)
“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings.”
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
Widely distributed to most tissues and rat milk at concentrations similar to blood
“Following oral administration to rats and monkeys, [14C]ubrogepant was approximately 23% bioavailable and was widely distributed to most tissues and milk (rat) at similar concentrations to blood.”
Modality-specific risk
Hepatotoxicity and coronary artery vasoconstriction potential
“In addition, the sponsor conducted studies to investigate the potential for ubrogepant to constrict human coronary arteries and to further assess the risk of hepatotoxicity.”
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
- 1 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 Ubrelvy 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: No adverse findings up to 160 mg/kg (6-month rat) and 175 mg/kg (9-month monkey) (FDA pharmacology/toxicology review, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month rhesus monkey (oral); recovery phase not stated
“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings.”
Pivotal GLP studies
6-month rat and 9-month rhesus monkey oral studies
“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”
DART package
Species: DART
Wistar rat (fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“A standard battery of reproductive and development toxicology studies was conducted for ubrogepant: fertility and early embryonic development (0, 20, 80, and 160 mg/kg), embryofetal development (0, 1.5, 5. 25, and 125 mg/kg), and pre- and postnatal development (0, 25, 60, and 160 mg/kg) in Wistar rat, and an embryofetal development in New Zealand White rabbit”
Reproductive & developmental
Rabbit EFD: embryofetal mortality; rat PPND: lower offspring body weight; both at maternally toxic doses
“In animal studies, adverse effects on embryofetal development were observed following administration of ubrogepant during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at doses greater than those used clinically and which were associated with maternal toxicity”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre- and postnatal development study in rat, ubrogepant, administered orally at doses of 0, 25, 60, and 160 mg/kg/day throughout gestation and lactation, resulted in reduced body weight at birth”
Carcinogenicity
Species: carcinogenicity
CD-1 mouse and Wistar rat (104-week oral)
“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”
Carcinogenicity model
104-week oral CD-1 mouse and Wistar rat; mouse study judged inadequate (AUC margin <25-fold MRHD)
“Ubrogepant was negative in 104-week mouse (up to 50 mg/kg) and rat (up to 100(M) and 150(F)) carcinogenicity studies, according to the FDA statistical analysis. However, the mouse study was not adequate because the safety margin based on AUC at the highest dose tested was less than 25-fold the MRHD.”
Carcinogenicity timing
104-week CD-1 mouse and Wistar rat studies completed before the marketing application
“In adequately designed and conducted 104-week oral carcinogenicity studies in CD-1 mouse (0, 5, 15, and 50 mg/kg/day) and Wistar rat (males: 0, 10, 30, and 100 mg/kg/day; females: 0, 10, 30, and 150 mg/kg/day), ubrogepant was negative for drug-related neoplasms.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse findings at highest doses: 34x (6-month rat) and 78x (9-month monkey) human AUC at MRHD 200 mg/day
“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings. The safety margins based on AUC at the highest doses tested were 34- and 78-fold in rat and monkey, respectively, relative to that at the maximum recommended human dose (MRHD) of 200 mg/day.”
NOAEL / key findings
No adverse findings up to 160 mg/kg (6-month rat) and 175 mg/kg (9-month monkey)
“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings.”
Efficacy evidenceopen answer page →
Efficacy evidence
Capsaicin-induced dermal vasodilation in rat, rabbit and monkey; CGRP-induced relaxation of human cranial arteries ex vivo
“In efficacy models, ubrogepant inhibited relaxation of capsaicin-induced dermal vasodilation (a CGRP mediated response) in the rat (EC50=3 nM), rabbit (EC60 20 µM), and monkey (EC50=3 pM), and inhibited of CGRP-induced relaxation of human cranial arteries dose dependently (up to ~25% at 1 µM).”
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
Characterized as CGRP receptor antagonist across species, with more potent binding and in vivo functional effects in human and rhesus monkey than rodents and rabbit
“The primary pharmacology studies conducted characterize ubrogepant as an antagonist at the mouse, rat, rabbit, rhesus monkey, and human CGRP receptors, with greater in vitro binding affinity and more potent in vivo functional (capsaicin-induced vasodilation) effects in human and rhesus monkey compared to mouse (binding data only), rat, and New Zealand White rabbit.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityQuestioned
Mouse 104-week carcinogenicity study inadequate: AUC margin at highest dose below 25-fold the MRHD
“However, the mouse study was not adequate because the safety margin based on AUC at the highest dose tested was less than 25-fold the MRHD.”
Similar precedents
Nurtec ODTSmall molecules · rimegepant · CGRP receptorMonkey + rodent · 39 wkQuliptaSmall molecules · atogepant · CGRP receptorMonkey + rodent · 39 wkZavzpretSmall molecules · zavegepant · CGRP receptorMonkey + rodent · 39 wkAjovyAntibodies · fremanezumab · CGRPMonkey + rodent · 26 wkEmgalityAntibodies · galcanezumab · CGRPMonkey + rodent · 26 wkVyeptiAntibodies · eptinezumab · CGRPMonkey + rodent · 26 wk