Zavzpret
zavegepant
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
“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”
Why that species
Monkey CGRP receptor binding affinity similar to human; far lower affinity in rodent, rabbit and dog
“similar binding affinity was observed to the CGRP receptors in cynomolgus (IC50 = 0.06 nM) and marmoset (IC50 = 0.13 nM) monkeys. In vitro binding affinity was substantially lower to the CGRP receptors in the other animal species tested (IC50 values of 500, 600, 8,700, 25,000, and 140,000 nM for beagle dog, guinea pig, rabbit, rat, and mouse, respectively).”
Surrogate molecule
No surrogate; the clinical compound was tested
“Monkey: zavegepant was administered at doses of 0, 7.5, 17, and 25 mg/day in the 4-week intranasal study, at doses of 0, 18, 27, and 36 mg/day in the 13-week study, and at doses of 0, 18, 36, and 45 mg/day in the 39-week study.”
Species: general tox
Sprague Dawley rat (4-, 13-, 26-week) and cynomolgus monkey (4-, 13-, 39-week), intranasal
“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”
Species: DART
Sprague Dawley rat and New Zealand White rabbit (subcutaneous)
“A standard battery of reproductive and developmental toxicology studies was conducted for zavegepant in Sprague Dawley rat and New Zealand White rabbit. The studies were conducted using subcutaneous administration to increase systemic exposure.”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and SD rat (2-year), intranasal
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
Surrogate used in
No surrogate used; monkey was the only pharmacologically relevant species
“Therefore, monkey was the only pharmacologically relevant species for on-target toxicities.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey intranasal studies
“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”
Route in tox
Intranasal; additional subcutaneous studies to increase systemic exposure
“Because systemic exposure was low (“generally <2%”) following IN dosing, additional studies were conducted using subcutaneous administration to increase systemic exposure (4- and 13-week in rat; 4-week in monkey).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and in vivo rat micronucleus assays
“Zavegepant was negative for mutagenicity and clastogenicity in an adequate battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, and in vivo rat micronucleus) assays.”
Carcinogenicity
26-week Tg.rasH2 mouse and up to 96-week rat intranasal studies: no drug-related tumors
“Intranasal administration of zavegepant (0, 0.3, 0.8, or 2.5 mg/day) to Tg.rasH2 mice for 26 weeks resulted in no evidence of drug-related tumors. Intranasal administration of zavegepant (0, 2, 9, or 18.8 mg/kg/day) to rats for up to 96 weeks resulted in no evidence of drug-related tumors.”
Reproductive & developmental
Rat and rabbit studies: no reproductive or developmental toxicity at ≥2000-fold human exposure
“Reproductive and developmental toxicology studies were conducted in SD rat and New Zealand White rabbit. There were no reproductive or developmental toxicities at doses resulting in drug exposures at least 2,000-fold higher than human exposure (i.e., AUC) at the proposed clinical dose.”
Safety pharmacology
No cardiovascular (monkey) or respiratory (rat) effects; hERG IC50 >30 µM
“There were no effects of BHV-3500 on cardiovascular or respiratory safety pharmacology endpoints in cynomolgus monkey or Sprague Dawley (SD) rat, respectively. The IC50 for hERG inhibition in transfected HEK293 cells was in excess of 30 µM.”
Genotox: Ames
Negative
“BHV-3500 was negative in an adequately conducted Ames assay.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Zavegepant was negative for mutagenicity and clastogenicity in an adequate battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, and in vivo rat micronucleus) assays.”
Genotox: in vivo
Rat micronucleus: negative
“Zavegepant was negative for mutagenicity and clastogenicity in an adequate battery of genetic toxicology (Ames, in vitro chromosomal aberration in Chinese hamster ovary cells, and in vivo rat micronucleus) assays.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 2-year SD rat (intranasal); both negative
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat intranasal studies completed before the marketing application; both negative
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
hERG / QT
hERG and SCN5A IC50 >30 µM; no ECG or cardiovascular effects in telemetered monkeys
“The IC50 values for hERG/IKr and SCN5A channels in stably transfected HEK293 cells were in excess of 30 µM.”
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 Zavzpret 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: Reversible nasal olfactory/respiratory epithelium degeneration in 13-week rat; rat intranasal NOAEL 12.5 mg/day (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Reversible nasal olfactory/respiratory epithelium degeneration in 13-week rat; rat intranasal NOAEL 12.5 mg/day
“The primary toxicity following IN administration in rat consisted of olfactory and respiratory epithelium degeneration and regeneration in the 13-week repeat dosing study which resolved over a 4-week recovery period. The NOAEL for IN administration in rat was 12.5 mg/day.”
Risksopen answer page →
Immune & cytokine safety
Non-dose-related lower spleen and thymus weights in monkey without histopathological correlates
“There were increases in the weight of adrenal glands, thyroid/parathyroid, and ovaries and decreases in spleen and thymus in BHV-3500 groups; however, the changes were not dose-related, and there were no histopathological correlates.”
Biodistribution & persistence
Minimal CNS penetration: plasma:olfactory bulb 500:1 and plasma:trigeminal nerve 180:1 after intranasal dosing in rat
“Following intranasal administration of 14C-zavegepant to rats, plasma:olfactory bulb and plasma:trigeminal nerve radioactivity ratios were 500:1 and 180:1, respectively, at 0.5 hours postdose.”
Modality-specific risk
Local nasal cavity epithelial toxicity (degeneration/regeneration, inflammation) with intranasal dosing
“Local toxicity (nasal cavity epithelium degeneration/regeneration, subacute inflammation) was observed at all doses in the 13-week study, which resulted in lower doses being used in the 26-week study.”
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 Zavzpret 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: Reversible nasal olfactory/respiratory epithelium degeneration in 13-week rat; rat intranasal NOAEL 12.5 mg/day (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week intranasal cynomolgus monkey study; recovery phase not stated
“Monkey: zavegepant was administered at doses of 0, 7.5, 17, and 25 mg/day in the 4-week intranasal study, at doses of 0, 18, 27, and 36 mg/day in the 13-week study, and at doses of 0, 18, 36, and 45 mg/day in the 39-week study.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey intranasal studies
“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”
DART package
Species: DART
Sprague Dawley rat and New Zealand White rabbit (subcutaneous)
“A standard battery of reproductive and developmental toxicology studies was conducted for zavegepant in Sprague Dawley rat and New Zealand White rabbit. The studies were conducted using subcutaneous administration to increase systemic exposure.”
Reproductive & developmental
Rat and rabbit studies: no reproductive or developmental toxicity at ≥2000-fold human exposure
“Reproductive and developmental toxicology studies were conducted in SD rat and New Zealand White rabbit. There were no reproductive or developmental toxicities at doses resulting in drug exposures at least 2,000-fold higher than human exposure (i.e., AUC) at the proposed clinical dose.”
PPND / ePPND: when
Two PPND studies in rat (subcutaneous) completed before the marketing application
“Two pre- and postnatal development studies were conducted in rat. In both studies, zavegepant was administered at doses of 0, 5, 10, and 20 mg/kg/day from GD 6 to lactation day (LD) 20.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and SD rat (2-year), intranasal
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 2-year SD rat (intranasal); both negative
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat intranasal studies completed before the marketing application; both negative
“A 26-week study in Tg.rasH2 mouse and a 2-year study in SD rat were conducted to assess the carcinogenic potential of BHV-3500. Both studies were negative for carcinogenicity.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 39-week intranasal, highest dose: ~8-fold (systemic) and ~12-fold (local) vs human at MRHD
“At the highest dose tested in the 39-week study, safety margins for local and systemic toxicity were approximately 12- and 8-fold, respectively.”
NOAEL / key findings
Reversible nasal olfactory/respiratory epithelium degeneration in 13-week rat; rat intranasal NOAEL 12.5 mg/day
“The primary toxicity following IN administration in rat consisted of olfactory and respiratory epithelium degeneration and regeneration in the 13-week repeat dosing study which resolved over a 4-week recovery period. The NOAEL for IN administration in rat was 12.5 mg/day.”
Efficacy evidenceopen answer page →
Efficacy evidence
Suppression of CGRP-induced facial blood flow in cynomolgus monkeys; in vitro receptor binding
“An in vivo pharmacology study indicated suppression of CGRP-induced facial blood flow in monkeys without vasoconstrictive effects on coronary or cerebral arteries (as measured by laser doppler).”
Why that model
CGRP receptor affinity ~10,000-fold lower in dog, rabbit and rat; similar in cynomolgus monkey
“In vitro primary pharmacology studies indicated similar affinity of BHV-3500 for human and cynomolgus monkey CGRP receptors; however, affinity was approximately 10,000-fold lower for dog, rabbit, and rat CGRP.”
Reviewer's view of the efficacy data
FDA: in vitro and in vivo studies characterize zavegepant as a selective CGRP receptor antagonist (IC50 0.04 nM)
“The results of in vitro and in vivo studies characterize zavegepant as a calcitonin gene-related peptide (CGRP) receptor antagonist (IC50 of 0.04 nM), with selectivity for CGRP compared to other members of the calcitonin receptor family”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted with a condition
Juvenile animal toxicology study deferred to a post-marketing requirement to support pediatric development
Why: Needed only for future pediatric development under PREA · Within the guideline
“The nonclinical data support approval of zavegepant for the proposed indication, with appropriate labeling. A PMR for a juvenile animal toxicology study is recommended, under PREA, to support clinical development for treatment of migraine in the pediatric population.”
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