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.”
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.”
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.”