Nurtec ODT
rimegepant
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
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Why that species
Monkey CGRP receptor affinity similar to human; rodent affinity >1,300-fold lower, so rat is insensitive
“Comparing activity across species, rimegepant exhibits similar receptor affinities at both human (Ki of 33 pM) and nonhuman primate (marmoset (92 pM) and cynomolgus monkey (60 pM)) CGRP receptors, with more than 1,300-fold less activity at dog (43 nM), rat (209 nM) and mouse (104 nM) CGRP receptors as compared to human.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Doses of 0, 5, 15, and 50 mg/kg were evaluated in the pivotal 9-month study; there were no adverse findings. The NOAEL for orally-administered rimegepant in monkey was 50 mg/kg.”
Species: general tox
Rat (6-month) and cynomolgus monkey (9-month)
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Species: DART
Rat and rabbit
“Reproductive toxicity studies conducted and rats and rabbits were considered adequate for assessment of possible rimegepant-induced effects on reproduction.”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague-Dawley rat (lifetime)
“The carcinogenic potential of rimegepant was assessed in a 26-week study in Tg.rasH2 mouse (0, 10, 100, or 300 mg/kg/day) and a lifetime study in Sprague-Dawley rat (0, 5, 20, or 45 mg/kg/day).”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Route in tox
Oral
“All studies used the oral application, the intended clinical route of administration of rimegepant.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus assays
“BHV-3000 was negative in Ames, chromosomal aberration, and rat bone marrow micronucleus assays.”
Carcinogenicity
26-week Tg.rasH2 mouse and 2-year rat: no drug-induced tumors
“Based on a review by the CDER Division of Biometrics, BHV-3000 did not induce tumor formation in the 26-week and 2-year carcinogenicity studies in TgRasH2 mice (0, 30, 100 300 mg/kg) and SD rats (0, 5, 15, 45 mg/kg), respectively.”
Reproductive & developmental
Rat fertility: uterine atrophy >25 mg/kg, reduced conception at 150 mg/kg; no embryofetal toxicity in rat or rabbit
“Two fertility studies in SD rat indicated uterine atrophy at doses greater than 25 mg/kg, and decreased conception and increased pre-implantation loss at 150 mg/kg. There was no embryofetal toxicity in rat or rabbit.”
Safety pharmacology
No CNS, cardiovascular or respiratory effects; hERG and sodium channel IC50 >30 µM
“There were no effects of BHV-3000 on CNS, cardiovascular, or respiratory safety pharmacology endpoints, and the IC50 for hERG or sodium ion channels was estimated to be in excess of 30 uM.”
Genotox: Ames
Negative
“Rimegepant was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, in vivo male Sprague-Dawley rat micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Rimegepant was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, in vivo male Sprague-Dawley rat micronucleus) assays.”
Genotox: in vivo
Rat micronucleus: negative
“Rimegepant was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, in vivo male Sprague-Dawley rat micronucleus) assays.”
Carcinogenicity model
Short-term Tg.rasH2 mouse and 2-year SD rat: not carcinogenic
“Rimegepant was not carcinogenic in a short-term study in hemizygous Tg.rasH2 mice and a 2 year lifespan study in Crl:CD(SD) rats.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 2-year rat completed before the marketing application
“Based on a review by the CDER Division of Biometrics, BHV-3000 did not induce tumor formation in the 26-week and 2-year carcinogenicity studies”
hERG / QT
hERG and sodium channel IC50 >30 µM; no cardiovascular safety pharmacology effects
“There were no effects of BHV-3000 on CNS, cardiovascular, or respiratory safety pharmacology endpoints, and the IC50 for hERG or sodium ion channels was estimated to be in excess of 30 uM.”
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 Nurtec ODT 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: Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases) (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases)
“based on liver vacuolation at all doses (0, 5, 20, or 45 mg/kg) in the 6-month study, a NOAEL was not established in rats. The primary toxicity in monkeys consisted of decreases in weight gain; based on this finding, the NOAEL for daily administration of BHV-3000 for 9 months was 15 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
No effects on the immune system in pivotal studies
“Further, no hormonal perturbation, histopathological changes in endocrine or reproductive organs or effects on the immune system were observed in pivotal non-clinical studies.”
Biodistribution & persistence
Wide extravascular distribution in pigmented and albino rats; likely melanin binding
“A single-dose tissue distribution study in pigmented and albino rats demonstrated that rimegepant is widely distributed extravascularly and likely binds to melanin.”
Modality-specific risk
Intravascular hemolysis/anemia in rat and monkey
“It is difficult to dismiss this finding as not drug-related, considering evidence of intravascular hemolysis in other studies of rimegepant in monkey and rat in the absence of microscopic findings.”
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
- Hypertension
- 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 Nurtec ODT 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: Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases) (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week (9-month) cynomolgus monkey (oral) with 28-day recovery
“9-Month Repeat Dose Toxicity and Toxicokinetic Study of BHV-3000 Hemisulfate in Cynomolgus Monkeys with a 28-Day Recovery Period”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
DART package
Species: DART
Rat and rabbit
“Reproductive toxicity studies conducted and rats and rabbits were considered adequate for assessment of possible rimegepant-induced effects on reproduction.”
Reproductive & developmental
Rat fertility: uterine atrophy >25 mg/kg, reduced conception at 150 mg/kg; no embryofetal toxicity in rat or rabbit
“Two fertility studies in SD rat indicated uterine atrophy at doses greater than 25 mg/kg, and decreased conception and increased pre-implantation loss at 150 mg/kg. There was no embryofetal toxicity in rat or rabbit.”
PPND / ePPND: when
PPND in rat completed before the marketing application but deficient; a new rat PPND study required after approval (PMR)
“Overall, the nonclinical data support approval of NDA 212728 (ODT) however, a pre- and postnatal development study, to include an adequate number of offspring for evaluation and a more rigorous neurobehavioral assessment, should be a post-marketing requirement (PMR).”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague-Dawley rat (lifetime)
“The carcinogenic potential of rimegepant was assessed in a 26-week study in Tg.rasH2 mouse (0, 10, 100, or 300 mg/kg/day) and a lifetime study in Sprague-Dawley rat (0, 5, 20, or 45 mg/kg/day).”
Carcinogenicity model
Short-term Tg.rasH2 mouse and 2-year SD rat: not carcinogenic
“Rimegepant was not carcinogenic in a short-term study in hemizygous Tg.rasH2 mice and a 2 year lifespan study in Crl:CD(SD) rats.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 2-year rat completed before the marketing application
“Based on a review by the CDER Division of Biometrics, BHV-3000 did not induce tumor formation in the 26-week and 2-year carcinogenicity studies”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey: ≥16x (males) and ≥24x (females) human AUC at clinical dose
“Safety margins to exposures (based on AUC) at the the clinical dose were obtained at ≥ 16 x for males and ≥ 24 x for females.”
NOAEL / key findings
Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases)
“based on liver vacuolation at all doses (0, 5, 20, or 45 mg/kg) in the 6-month study, a NOAEL was not established in rats. The primary toxicity in monkeys consisted of decreases in weight gain; based on this finding, the NOAEL for daily administration of BHV-3000 for 9 months was 15 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Marmoset hCGRP-induced facial blood flow: 75-80% inhibition (target engagement in normal animals)
“Rimegepant effectively antagonised the hCGRP-induced increases in marmoset facial blood flow showing 75% to 80% inhibition at plasma levels of ~700 nM (or 374 ng/mL).”
Why that model
Human-like CGRP receptor affinity only in primates; >1,300-fold lower activity at dog, rat and mouse receptors
“Comparing activity across species, rimegepant exhibits similar receptor affinities at both human (Ki of 33 pM) and nonhuman primate (marmoset (92 pM) and cynomolgus monkey (60 pM)) CGRP receptors, with more than 1,300-fold less activity at dog (43 nM), rat (209 nM) and mouse (104 nM) CGRP receptors as compared to human.”
Reviewer's view of the efficacy data
EMA: pharmacodynamic data sufficiently discussed by the applicant
“Pharmacodynamic data of rimegepant were sufficiently discussed by the applicant.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
Rat pre- and postnatal development study deficient (too few offspring, weak neurobehavioral assessment); repeat required postmarketing
Why: Nonclinical data support approval; new PPND study with adequate offspring numbers and more rigorous neurobehavioral assessment as PMR
“The battery of nonclinical studies conducted to support clinical development and a marketing application for rimegepant was adequate, except for the completed pre- and postnatal development study in rat, which had several deficiencies.”
“Overall, the nonclinical data support approval of NDA 212728 (ODT) however, a pre- and postnatal development study, to include an adequate number of offspring for evaluation and a more rigorous neurobehavioral assessment, should be a post-marketing requirement (PMR).”
Juvenile toxAccepted with a conditionBeyond the letter
No juvenile animal toxicity study before approval; required postmarketing under PREA
Why: Needed to support pediatric development under 12 years of age
“In addition, a juvenile animal toxicology study should be a PMR to support clinical development in pediatric patients <12 years of age, under PREA.”
Similar precedents
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