Vyepti
eptinezumab
Species
MonkeyRatRabbit
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat, cynomolgus monkey and rabbit
“Toxicity studies with eptinezumab were conducted in rats, cynomolgus monkeys and rabbits. These species are considered pharmacologically relevant based on the affinity and functional activity of eptinezumab against CGRP from these species.”
Why that species
High affinity and specificity for rat, rabbit, monkey and human α- and β-CGRP; no off-target binding to related peptides
“Eptinezumab has high affinity and specificity for rat, rabbit, monkey, and human α- and β-CGRP without off target binding to amylin, calcitonin, adrenomedulin, or intermedin/ adrenomedulin-2.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rat, rabbit and cynomolgus monkey
“Toxicity studies with eptinezumab were conducted in rats, cynomolgus monkeys and rabbits.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The Division agreed that only a monkey chronic (6-month) study was needed (email correspondence, April 4, 2013).”
Pivotal GLP studies
Cynomolgus monkey 28-day IV Q2W (up to 100 mg/kg) and 6-month IV Q2W (up to 150 mg/kg)
“In monkey, eptinezumab was tested in 28-day (0, 10, 30, and 100 mg/kg IV Q2W) and 6-month (0, 20, 50, and 150 mg/kg Q2W) studies.”
Route in tox
IV (bolus)
“A 6-month repeat dose study of ALD403 by intravenous bolus injection in Cynomolgus monkeys with a 3-month recovery period”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted; weight-of-evidence assessment: CGRP blockade would counter pro-angiogenic/immunosuppressive effects, low risk
“Since blockade of CGRP would prevent these effects, the carcinogenic risk associated with eptinezumab is considered low.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: no adverse effects; NOAEL 150 mg/kg/week (highest dose)
“The NOAEL was 150 mg/kg/week in the rat fertility, rat and rabbit embryofetal development, and rat pre- and postnatal studies.”
Safety pharmacology
Incorporated into rat and monkey toxicology studies; no neurological, cardiovascular or respiratory effects
“Eptinezumab had no effect on the neurological, cardiovascular, and respiratory systems when given up to 100 mg/kg/week or on the neurological and cardiovascular systems at up to 150 mg/kg once every 2 weeks.”
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 Vyepti 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 monoclonal antibodies 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 effects; NOAEL 100 mg/kg/week (rat 4-week) and 150 mg/kg every 2 weeks (monkey 6-month) (FDA pharmacology/toxicology review, p. 8)
NOAEL / key findings
No adverse effects; NOAEL 100 mg/kg/week (rat 4-week) and 150 mg/kg every 2 weeks (monkey 6-month)
“No adverse effects of IV eptinezumab were observed in either the rat 4-week or monkey 6-month general toxicology studies; the NOAELs were determined to be 100 mg/kg/week and 150 mg/kg every 2 weeks, respectively.”
Risksopen answer page →
Immune & cytokine safety
Anaphylactoid reaction in a monkey associated with high ADA; animal immunogenicity not considered predictive of clinical risk
“This anaphylactoid reaction was associated with the presence of high levels of ADA. As immunogenicity to a human protein in animals is not predictive for clinical immunogenicity, the finding is not considered indicative of a clinical risk.”
Biodistribution & persistence
TCR: staining mainly of blood vessels (endothelium, smooth muscle, adventitia)
“In a tissue cross-reactivity study, eptinezumab staining was generally in blood vessels including endothelium, smooth muscle, and adventitia.”
Modality-specific risk
Theoretical cardiovascular and pregnancy (pre-eclampsia) risks of blocking CGRP signalling
“specific theoretical risks associated with blockade of CGRP-dependent signalling (i.e. cardiovascular outcomes in patients with pre-existing myocardial infarction, cerebro-vascular accident, transient ischemic attack, angina, unstable and poorly controlled hypertension; use in pregnancy including those at risk of pre-eclampsia)”
Similar precedents
Ajovyfremanezumab · CGRPMonkey + rodent · 26 wkEmgalitygalcanezumab · CGRPMonkey + rodent · 26 wkAimovigerenumab · CGRP receptorMonkey only · 26 wkAduhelmaducanumab · Aggregated amyloid-βMonkey + rodent · 26 wkKisunladonanemab · Amyloid-β (N3pG)Monkey + rodent · 22 wkBriumviublituximab · CD20Monkey only · 26 wk