Ajovy
fremanezumab
Species
MonkeyRat
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 and cynomolgus monkey (chronic study in monkey only)
“Because the shorter duration studies in rat and monkey demonstrated no toxicity, the chronic study was conducted only in cynomolgus monkey.”
Why that species
Pharmacologically active in rat, rabbit, monkey and human in binding and functional in vitro assays
“Fremanezumab is pharmacologically active in rat, rabbit, monkey, and human, as characterized in a series of binding and functional in vitro assays.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rat and cynomolgus monkey
“General toxicology studies were conducted in rat and cynomolgus monkeys. In general, fremanezumab was well tolerated, with no significant adverse effects in either species.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Repeat-dose toxicity studies with the duration of 1 month and 3 months were conducted both in rats and monkeys; the pivotal 26-week study was only conducted in monkeys.”
Pivotal GLP studies
Sprague-Dawley rat 1- and 3-month; cynomolgus monkey 1-, 3- and 6-month
“The pivotal (GLP) toxicity studies were conducted in Sprague-Dawley rat (1- and 3-month) and cynomolgus monkey (1-, 3-, and 6-month).”
Route in tox
IV and SC (weekly)
“In the 3-month study in cynomolgus monkeys, animals received weekly IV or SC injection of fremanezumab at doses levels of up to 300 mg/kg.”
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 (CGRP knockout data, CGRP biology, tox findings) judged studies unnecessary
“Based on published studies in CGRP knockout animals and on the biological activity of CGRP (e.g., promotion of angiogenesis) and on the results from the sponsor’s studies of fremanezumab, it was concluded that standard carcinogenicity studies of fremanezumab were not needed.”
Reproductive & developmental
Rat fertility + EFD, rabbit EFD and rat PPND: no adverse effects on fertility or pregnancy outcome
“Reproductive and developmental toxicity was assessed in a fertility + EFD study in rats, a EFD study in rabbits and a PPND study in rats. These studies have not revealed any adverse effects on fertility and pregnancy outcome.”
Safety pharmacology
Rat CNS/respiratory: no adverse effects; monkey IV cardiovascular assessment: minimal effects
“No adverse effects on CNS or respiratory parameters were observed in rat following acute subcutaneous (SC) doses of fremanezumab (0, 100, and 300 mg/kg). Minimal cardiovascular effects were observed in monkey following intravenous (IV) bolus doses of 0 or 100 mg/kg”
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 Ajovy 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: Chronic monkey study, weekly SC up to 300 mg/kg: no adverse effects except injection-site inflammation (FDA pharmacology/toxicology review, p. 71)
NOAEL / key findings
Chronic monkey study, weekly SC up to 300 mg/kg: no adverse effects except injection-site inflammation
“Monkeys were dosed weekly via SC injection at dose levels of up to 300 mg/kg for 25 weeks, followed by a 16-week recovery period. No adverse effects except injection site inflammation were observed at any dose.”
Risksopen answer page →
Immune & cytokine safety
Ciliary vessel inflammation with immune complex deposition in a monkey study (hypersensitivity-type); not reproduced in the 6-month study
“The inflammation was accompanied by increased monocytes and deposition of immune complexes (C3 complement, IgG and/or IgM). These findings were not reproduced in the 6 month study.”
Biodistribution & persistence
Low Vd (0.07-0.14 L/kg) across species; tissue distribution studies not conducted
“Vd was low in all species (0.07-0.14 L/kg). Tissue distribution and metabolism studies were not requested or conducted.”
Modality-specific risk
Cardiovascular risk of long-term CGRP antagonism (loss of vasodilation), especially with cardiovascular risk factors
“Because of the potent vasodilatory properties of CGRP, concerns were raised regarding long-term antagonism of the CGRP in humans, particularly in patients with cardiovascular risk factors.”
Similar precedents
Emgalitygalcanezumab · CGRPMonkey + rodent · 26 wkVyeptieptinezumab · 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