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.”
Species: general tox
Rat (1- and 3-month) and 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).”
Species: DART
Rat (fertility + EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicity was assessed in a fertility + EFD study in rats, a EFD study in rabbits and a PPND study in rats.”
Species: carcinogenicity
Not conducted; weight-of-evidence assessment judged standard 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.”
Surrogate used in
No surrogate used; clinical antibody active in rat, rabbit and monkey
“Fremanezumab is pharmacologically active in rat, rabbit, monkey, and human, as characterized in a series of binding and functional in vitro assays.”
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”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted; carcinogenic risk assessment per ICH S6(R1) judged risk low
“No carcinogenicity studies have been conducted, in accordance with ICH S6(R1) and a scientific advice.”
Carcinogenicity timing
Not required; waiver of carcinogenicity assessment granted
“Carcinogenicity assessments were not conducted for fremanezumab. The sponsor submitted a request for waiver of the carcinogenicity assessment. which was granted.”
hERG / QT
No hERG assay; no meaningful effect on heart rate, blood pressure or ECG in telemetered monkeys at 100 mg/kg
“Fremanezumab (100 mg/kg) had no meaningful effect on changes in heart rate, blood pressure, ECG recordings or body temperature in conscious telemetered monkeys.”
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
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: 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.”
Anti-drug antibodies: animals
Monkey 6-month: 5/28 (17.8%) ADA-positive with low titers and no effect on exposure; ADAs affected exposure in shorter studies
“In the six month study in monkeys (SC injections once weekly) 5 out of 28 animals (17.8%) dosed with fremanezumab had treatment-related ADA response with relative low titer values, which apparently did not influence exposure”
Anti-drug antibodies: patients
0.4% (6/1701) in 3-month placebo-controlled studies; 1 of 6 neutralizing
“In 3-month, placebo-controlled studies in adult patients, treatment-emergent anti-drug antibodies were observed in 0.4% (6 out of 1701) AJOVY-treated patients. One of the 6 patients developed anti-AJOVY neutralizing antibodies at Day 84.”
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 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
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: Chronic monkey study, weekly SC up to 300 mg/kg: no adverse effects except injection-site inflammation (FDA pharmacology/toxicology review, p. 71)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey SC study (once weekly) with 16-week recovery
“Study title: 26-week subcutaneous injection chronic toxicity and toxicokinetic study with once-weekly dosing of LBR-101 in cynomolgus monkeys with a 16- week recovery phase”
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).”
DART package
Species: DART
Rat (fertility + EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicity was assessed in a fertility + EFD study in rats, a EFD study in rabbits and a PPND study in rats.”
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.”
PPND / ePPND: when
PPND in rat: completed before the marketing application
“Pre- and postnatal development was evaluated in rat.”
Carcinogenicity
Species: carcinogenicity
Not conducted; weight-of-evidence assessment judged standard 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.”
Carcinogenicity model
Not conducted; carcinogenic risk assessment per ICH S6(R1) judged risk low
“No carcinogenicity studies have been conducted, in accordance with ICH S6(R1) and a scientific advice.”
Carcinogenicity timing
Not required; waiver of carcinogenicity assessment granted
“Carcinogenicity assessments were not conducted for fremanezumab. The sponsor submitted a request for waiver of the carcinogenicity assessment. which was granted.”
Safety marginopen answer page →
Safety margin at NOAEL
Cmax exposure multiples 2.3-43x (IV) and 2.2-227x (SC) vs human; may be overestimated due to animal accumulation
“Exposure multiples (based on Cmax) varied from 2.3-43 for i.v. administrations and from 2.2-227 for s.c. administrations.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat post-concussion and medication-overuse headache models; vasodilation models in rat and cynomolgus monkey
“Fremanezumab was tested in 2 rat models of headache (post-concussion headache and medication overuse headache) in which pain-related behaviors were measured after application of a presumed migraine stimulus.”
Why that model
No complete animal model of migraine; vasodilation and pain models used instead
“No complete animal model of migraine is available. Restriction of blood flow via inhibition of CGRP after administration of fremanezumab was assessed in several animal models, including animal models of pain.”
Reviewer's view of the efficacy data
FDA: models show modulation of CGRP activity, but relevance for predicting human migraine efficacy unknown
“These studies indicate that fremanezumab can modify presumed CGRP activity. How relevant these models are for predicting efficacy in human migraine is not known.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies for a chronic migraine therapy; weight-of-evidence assessment (CGRP knockout data, CGRP biology, tox findings) instead
Why: CGRP knockout data, CGRP biology and own tox results; carcinogenic risk of CGRP inhibition considered low, in line with ICH S6(R1) · Weight of evidence · Within the guideline
“The sponsor was asked to provide a weight-of-evidence evaluation of the carcinogenic potential of fremanezumab. 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.”
“However, as fremanezumab is intended for long-term treatment, in line with ICH S6(R1) a carcinogenicity risk assessment based on review of relevant data on CGRP functions from current literature has been provided. Based on this review, the carcinogenic risk for CGRP inhibition is considered low”
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