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.”
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.”
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 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: 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”