Aimovig
erenumab
Species
Monkey
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
Cynomolgus monkey only
“The pivotal, GLP-compliant toxicology studies were conducted in cynomolgus monkey, the only biologically relevant species”
Why that species
High affinity for monkey and human CGRP-R; no affinity for rodent CGRP-R or related family members
“Erenumab has high affinity for the monkey and human CGRP-R, but not for rodent CGRP-R or closely related CGRP-R family members.”
Surrogate molecule
No surrogate; the clinical antibody was tested in monkeys (no pharmacological activity in other species)
“General toxicology studies were conducted exclusively in monkeys, due to a lack of pharmacological activity in other species.”
Species: general tox
Cynomolgus monkey only (no pharmacological activity in other species)
“General toxicology studies were conducted exclusively in monkeys, due to a lack of pharmacological activity in other species.”
Species: DART
Cynomolgus monkey (single enhanced PPND study); no separate fertility study
“The reproductive and developmental toxicology package consisted of a single enhanced PPND study in monkey, with dosing at 0 and 50 mg/kg”
Species: carcinogenicity
Not conducted (waived; erenumab inactive in rodents)
“Carcinogenicity studies were waived, based on the lack of erenumab activity in rodents, histopathological data from the submitted toxicology studies showing no carcinogenic risk factors (i.e. hyperplasia or neoplasia)”
Surrogate used in
No surrogate used; clinical antibody tested in monkeys only
“General toxicology studies were conducted exclusively in monkeys, due to a lack of pharmacological activity in other species.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the pivotal 3- and 6-month toxicity study with 15-week recovery period, SC doses of 0, 25, and 150 mg/kg were administered 2x per week (4/sex/group).”
Pivotal GLP studies
Monkey: 1-month IV with 4-month recovery; combined 3- and 6-month study; enhanced pre- and postnatal development study
“the pivotal (1- mo/acute IV + 4-month recovery; combined 3- and 6-month; enhanced pre- and postnatal development [ePPND]) studies were adequate by design and conduct”
Route in tox
Subcutaneous and intravenous
“SC doses of 0, 25, 75, 100, and 225 mg/kg were administered 2x per week or a single IV dose of 0 or 100 mg/kg was administered”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“no genotoxicity studies have been conducted, in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted; waived (no erenumab activity in rodents; no hyperplasia or neoplasia in toxicology studies)
“Carcinogenicity studies were waived, based on the lack of erenumab activity in rodents, histopathological data from the submitted toxicology studies showing no carcinogenic risk factors (i.e. hyperplasia or neoplasia)”
Reproductive & developmental
Monkey ePPND study: unremarkable results; NOAEL 50 mg/kg
“The results from the enhanced PPND study were unremarkable; therefore, the NOAEL was 50 mg/kg.”
Safety pharmacology
Telemetry study in monkeys (0, 25 or 225 mg/kg SC): no adverse cardiovascular, pulmonary or neurobehavioral effects
“In a safety pharmacology study, telemetry-instrumented conscious monkeys treated with 0, 25, or 225 mg/kg (SC) erenumab (6 males/group) showed no adverse cardiovascular, pulmonary, or neurobehavioral effects.”
Genotox: Ames
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted, in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted, in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted, in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted; rodent assays not feasible (no rodent activity) and monkey not appropriate for tumorigenic risk
“These assays are not feasible for AMG 334 because it is a monoclonal antibody that does not have biologic activity in rodents. AMG 334 has biologic activity in the cynomolgus monkey, but this species is not an appropriate model for evaluation of tumorigenic risk.”
Carcinogenicity timing
Not required: carcinogenicity study waiver granted
“A carcinogenicity study waiver was granted because erenumab is not active in rodents and the literature and submitted toxicity studies indicate that erenumab has a low potential for carcinogenicity.”
hERG / QT
No hERG; monkey telemetry: no arrhythmias, ECG waveform, QRS or QTc changes
“There were no AMG 334-related arrhythmias or changes in ECG waveform. There were no AMG 334-related changes in QRS duration or QTc interval.”
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 Aimovig 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: NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human (FDA pharmacology/toxicology review, p. 5)
NOAEL / key findings
NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human
“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times”
Risksopen answer page →
Immune & cytokine safety
ADA in 3 low-dose monkeys reduced drug exposure (Cmax and AUC)
“ADA was also observed in 3 LD animals, which resulted in reduced drug exposures (Cmax and AUC0-7d).”
Biodistribution & persistence
Volume of distribution typical of a monoclonal antibody, suggesting limited extravascular distribution
“Volume of distribution typical of a monoclonal antibody suggesting limited extravascular distribution.”
Modality-specific risk
Cardiovascular risk of chronic CGRP antagonism, as CGRP is a potent vasodilator
“Because CGRP is known to be involved in regulation of the cardiovascular system and to be a potent vasodilator, concerns were raised regarding potential adverse effects of chronic CGRP antagonism in humans”
Anti-drug antibodies: animals
Monkey ADA coincided with lower drug levels in some animals, only at low doses; kinetics at relevant doses not compromised
“ADAs detected coincidental with lower drug concentrations in some animals; effects on systemic exposure were only apparent at low doses so an assessment of the kinetics at pharmacologically and toxicologically relevant doses was not compromised.”
Anti-drug antibodies: patients
6.2% (70 mg monthly; 2 neutralizing) and 2.6% (140 mg monthly; none neutralizing) in controlled studies
“In controlled studies with AIMOVIG [see Clinical Studies (14) ] , the incidence of anti-erenumab-aooe antibody development was 6.2% (48/778) in patients receiving AIMOVIG 70 mg once monthly (2 of whom had in vitro neutralizing activity) and 2.6% (13/504) in patients receiving AIMOVIG 140 mg once monthly (none of whom had in vitro neutralizing activity).”
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 Aimovig 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: NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human (FDA pharmacology/toxicology review, p. 5)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey SC study (combined 3- and 6-month) with 15-week recovery
“In the pivotal 3- and 6-month toxicity study with 15-week recovery period, SC doses of 0, 25, and 150 mg/kg were administered 2x per week (4/sex/group).”
Pivotal GLP studies
Monkey: 1-month IV with 4-month recovery; combined 3- and 6-month study; enhanced pre- and postnatal development study
“the pivotal (1- mo/acute IV + 4-month recovery; combined 3- and 6-month; enhanced pre- and postnatal development [ePPND]) studies were adequate by design and conduct”
DART package
Species: DART
Cynomolgus monkey (single enhanced PPND study); no separate fertility study
“The reproductive and developmental toxicology package consisted of a single enhanced PPND study in monkey, with dosing at 0 and 50 mg/kg”
Reproductive & developmental
Monkey ePPND study: unremarkable results; NOAEL 50 mg/kg
“The results from the enhanced PPND study were unremarkable; therefore, the NOAEL was 50 mg/kg.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application, no adverse findings
“An enhanced PPND study conducted in monkey did not reveal any adverse findings.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waived; erenumab inactive in rodents)
“Carcinogenicity studies were waived, based on the lack of erenumab activity in rodents, histopathological data from the submitted toxicology studies showing no carcinogenic risk factors (i.e. hyperplasia or neoplasia)”
Carcinogenicity model
Not conducted; rodent assays not feasible (no rodent activity) and monkey not appropriate for tumorigenic risk
“These assays are not feasible for AMG 334 because it is a monoclonal antibody that does not have biologic activity in rodents. AMG 334 has biologic activity in the cynomolgus monkey, but this species is not an appropriate model for evaluation of tumorigenic risk.”
Carcinogenicity timing
Not required: carcinogenicity study waiver granted
“A carcinogenicity study waiver was granted because erenumab is not active in rodents and the literature and submitted toxicity studies indicate that erenumab has a low potential for carcinogenicity.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 3/6-month NOAEL (150 mg/kg twice weekly) >100x human AUC at 140 mg QM; ePPND NOAEL ~17x
“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times that anticipated in humans at the maximum recommended dose of 140 mg QM.”
NOAEL / key findings
NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human
“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times”
Efficacy evidenceopen answer page →
Efficacy evidence
Capsaicin-induced dermal blood flow inhibition in normal cynomolgus monkeys; no animal migraine model
“In vivo activity was demonstrated in a cynomolgus model of capsaicin induced increase in dermal blood flow, an effect mediated at least partly by CGRP. There are no animal migraine models.”
Why that model
No animal migraine models exist, so therapeutic evidence derives from clinical data
“There are no animal migraine models. Therefore, all evidence for a therapeutic effect is derived from clinical data.”
Reviewer's view of the efficacy data
EMA: primary pharmacodynamics programme considered appropriate
“The primary pharmacodynamics program has been appropriate.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic migraine therapy; waiver granted
Why: Erenumab not active in rodents; literature and toxicity studies indicate low carcinogenic potential · No relevant species · Weight of evidence
“A carcinogenicity study waiver was granted because erenumab is not active in rodents and the literature and submitted toxicity studies indicate that erenumab has a low potential for carcinogenicity.”
Juvenile toxAccepted with a conditionBeyond the letter
No juvenile animal toxicity study before approval; recommended as a postmarketing requirement
Why: Needed to support expanded clinical trials in pediatric patients
“A PMR for a juvenile animal toxicology study to support expanded clinical trials in pediatric patients is recommended.”
“Therefore, the nonclinical studies of AMG 334 conducted by the sponsor are considered adequate to support approval of the BLA, with no nonclinical post-marketing requirement to assess potential cardiovascular risk.”
Safety pharmacologyQuestioned
Monkey telemetry respiratory assessment limited to respiratory rate, without tidal volume or oxygen saturation
“The respiratory assessment was inadequate because the assessment of respiratory rate was not supported by other measures of respiratory function, such as tidal volume or hemoglobin oxygen saturation.”
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