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.”
Species: general tox
Rat and cynomolgus monkey (up to 28 days in both; chronic study in monkey only)
“General toxicity of eptinezumab was evaluated in single-dose and repeat-dose studies in rats and cynomolgus monkeys. Short-term studies (up to 28 days) were conducted in both species while the chronic toxicity was evaluated in cynomolgus only.”
Species: DART
Rat (fertility, EFD, pre- and postnatal development) and rabbit (EFD)
“A standard battery of reproductive and developmental toxicology studies was conducted in Sprague-Dawley rat (fertility and early embryonic development, embryofetal development (EFD), and pre- and postnatal development) and New Zealand White rabbit (EFD).”
Species: carcinogenicity
Not conducted; rodent studies not required because rat anti-drug antibodies precluded meaningful long-term studies
“(A chronic toxicity study in a second species (rat) and rodent carcinogenicity studies were not required, primarily because of data demonstrating development of anti-drug antibodies in rat that precluded conduct of meaningful long-term studies.)”
Surrogate used in
No surrogate used; eptinezumab cross-reacts and was tested in rat, 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.”
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.”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted; product-specific carcinogenicity risk assessment (nonclinical data plus literature on CGRP in tumorigenesis)
“In accordance with ICH S6(R1) the applicant has provided a product-specific carcinogenicity risk assessment taking into account non-clinical data for eptinezumab and a literature review on the potential role of CGRP in tumorigenesis and its effect on the immune system.”
Carcinogenicity timing
Not required: FDA Division accepted justification not to conduct studies
“The Division accepted the justification from the sponsor not to conduct carcinogenicity studies (DARRTs IND 114,647; January 27, 2016).”
hERG / QT
No standalone studies; no neurological, cardiovascular or respiratory effects in rat and monkey toxicity studies
“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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)”
Anti-drug antibodies: animals
One low-dose monkey died of an anaphylactoid reaction associated with high ADA
“One low-dose female exhibited an anaphylactoid-like reaction and died within approximately 30 minutes after eptinezumab administration on Day 71 (6th dose). This anaphylactoid reaction was associated with the presence of high levels of ADA.”
Anti-drug antibodies: patients
Study 1: ADA in 20.6% (92/447) of patients; 41.3% of these neutralizing
“In patients receiving VYEPTI 100 mg or 300 mg every 3 months, the incidence of anti-eptinezumab-jjmr antibody development in Study 1 (up to 56 weeks) was 20.6% (92/447), and 41.3% (38/92) of those patients developed anti-eptinezumab-jjmr neutralizing antibodies.”
Label warnings
- Hypersensitivity Reactions
- Constipation with Serious Complications
- Hypertension
- Raynaud’s Phenomenon
Hypersensitivity & infusion reactionsGastrointestinalCardiovascular
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 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey (IV bolus) with 3-month recovery
“A 6-month repeat dose study of ALD403 by intravenous bolus injection in Cynomolgus monkeys with a 3-month recovery period”
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.”
DART package
Species: DART
Rat (fertility, EFD, pre- and postnatal development) and rabbit (EFD)
“A standard battery of reproductive and developmental toxicology studies was conducted in Sprague-Dawley rat (fertility and early embryonic development, embryofetal development (EFD), and pre- and postnatal development) and New Zealand White rabbit (EFD).”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre- and postnatal development study (0, 75, and 150 mg/kg Q6), no adverse changes were noted; therefore, the NOAEL was the HD.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rodent studies not required because rat anti-drug antibodies precluded meaningful long-term studies
“(A chronic toxicity study in a second species (rat) and rodent carcinogenicity studies were not required, primarily because of data demonstrating development of anti-drug antibodies in rat that precluded conduct of meaningful long-term studies.)”
Carcinogenicity model
Not conducted; product-specific carcinogenicity risk assessment (nonclinical data plus literature on CGRP in tumorigenesis)
“In accordance with ICH S6(R1) the applicant has provided a product-specific carcinogenicity risk assessment taking into account non-clinical data for eptinezumab and a literature review on the potential role of CGRP in tumorigenesis and its effect on the immune system.”
Carcinogenicity timing
Not required: FDA Division accepted justification not to conduct studies
“The Division accepted the justification from the sponsor not to conduct carcinogenicity studies (DARRTs IND 114,647; January 27, 2016).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey chronic study, high dose: exposure >100x maximum clinical exposure
“In the chronic toxicity study, exposure in the high-dose group was > 100x greater than the maximum clinical exposure.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Capsaicin- or CGRP-induced dermal blood flow increase in rats, cynomolgus monkeys and rabbits
“In vivo activity of eptinezumab was demonstrated in a model of capsaicin-induced increase in dermal blood flow in rats and cynomolgus monkeys and a model of vasodilation induced intradermal injection of CRGP in rabbits.”
Why that model
No animal models of migraine exist; therapeutic evidence comes from clinical data
“There are no animal models for migraine; thus, the evidence for a therapeutic effect are derived from the clinical data.”
Reviewer's view of the efficacy data
FDA: high affinity for alpha- and beta-CGRP and effective antagonism of CGRP activity shown
“In conclusion, eptinezumab was shown to have high affinity for α- and β-CGRP and to effectively antagonize CGRP activity.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
Chronic toxicity in cynomolgus monkey only; no chronic rat study because rat anti-drug antibodies precluded meaningful long-term studies
Why: Anti-drug antibodies in rats precluded meaningful long-term studies; acceptable per ICH S6(R1) · Within the guideline · Pharmacology or kinetics
“(A chronic toxicity study in a second species (rat) and rodent carcinogenicity studies were not required, primarily because of data demonstrating development of anti-drug antibodies in rat that precluded conduct of meaningful long-term studies.)”
“Short-term studies (up to 28 days) were conducted in both species while the chronic toxicity was evaluated in cynomolgus only. This is acceptable in accordance with ICH S6(R1).”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; product-specific carcinogenicity risk assessment instead
Why: CGRP effects would support tumour growth, so CGRP blockade gives low carcinogenic risk · Weight of evidence · Pharmacology or kinetics
“The Division accepted the justification from the sponsor not to conduct carcinogenicity studies (DARRTs IND 114,647; January 27, 2016).”
“Both factors would support tumour growth. Since blockade of CGRP would prevent these effects, the carcinogenic risk associated with eptinezumab is considered low.”
Juvenile toxAccepted with a conditionBeyond the letter
Planned juvenile animal toxicity study not submitted before approval; required postmarketing
Why: Supports later pediatric clinical studies under PREA · Other reason
“To support clinical studies under PREA, the sponsor planned to conduct a juvenile animal toxicology study (Agreed iPSP Agreement letter, December 21, 2018); however, the study report has not been submitted. The study should be completed as a post-marketing requirement.”
Safety pharmacologyVerdict not stated
Safety pharmacology within toxicity studies lacked a functional observational battery; only respiratory rate evaluated
“vascular (Studies ALD403-003-TOX, ALD403-015-TOX, and ALD403-055-TOX), and respiratory (ALD403-015-TOX) endpoints were evaluated in single and repeat dose toxicology studies, although an FOB, or equivalent was not conducted and only respiratory rate evaluated.”
Safety marginVerdict not stated
Embryo-fetal studies collected only 5-minute post-dose concentrations; labeled margins based on mg/kg dose, not exposure
“Plasma exposure data at 150 mg/kg (collected in the pivotal EFD studies) were limited to mean concentrations at 5 min postdose: 4473 and 4116 µg/mL in rat and rabbit, respectively. Therefore, safety margins for labeling must rely on interspecies comparisons based on dose (mg/kg).”
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