Aduhelm
aducanumab
Species
MonkeyRatMouse
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 and transgenic Tg2576 mouse (murine surrogate and aducanumab); rat for reproductive studies
“The toxicology of aducanumab was adequately assessed in general toxicity studies in monkey and Tg2576 mouse.”
Why that species
Target is aggregated Aβ, absent in rodents and non-aged monkeys, so neither rat nor monkey is fully relevant
“Neither rat nor monkey is a particularly relevant species for general toxicity because of the lack of aggregated amyloid in rodent or non-aged monkey.”
Surrogate molecule
Yes: murine chimeric analog ch12F6A, used for 13-week and 6-month toxicity studies in aged Tg2576 mice
“In Tg2576 mouse, ch12F6A was administered for 13 weeks (0, 10, 70, or 500 mg/kg) or 6 months (0, 10, 40, or 250 mg/kg) weekly by intravenous injection; in each study, a separate group received aducanumab (500 or 250 mg/kg, respectively) according to the same regimen.”
Species: general tox
Cynomolgus monkey and aged Tg2576 transgenic mouse
“The toxicology of aducanumab was adequately assessed in general toxicity studies in monkey and Tg2576 mouse.”
Species: DART
Rat (fertility and early embryonic, embryofetal, pre/postnatal development)
“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”
Species: carcinogenicity
Not conducted (target aggregated Aβ absent in wild-type rodents)
“Carcinogenicity studies of aducanumab were not conducted because its target, aggregated Aβ, is not present in wild-type rodents.”
Surrogate used in
Yes: murine chimeric analog ch12F6A in Tg2576 mice for 13-week and 6-month toxicity (aducanumab arm included)
“In Tg2576 mouse, ch12F6A was administered for 13 weeks (0, 10, 70, or 500 mg/kg) or 6 months (0, 10, 40, or 250 mg/kg) weekly by intravenous injection; in each study, a separate group received aducanumab (500 or 250 mg/kg, respectively) according to the same regimen.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“There were no clear drug-related adverse effects in the GLP 6-month study of ch12F6A (0, 10, 40, or 250 mg/kg/week IV) or aducanumab (250 mg/kg/week IV) in aged Tg2576 mice.”
Pivotal GLP studies
Chronic Tg2576 mouse study with murine analog ch12F6A; 4-week monkey and 13-week Tg2576 mouse studies
“toxicity of the murine analog (ch12F6A) was tested in the Tg2576 mouse; shorter-duration toxicity studies were conducted in monkey (4-week) and Tg2576 mouse (13-week).”
Route in tox
IV (weekly slow bolus)
“In Tg2576 mouse, ch12F6A was administered for 13 weeks (0, 10, 70, or 500 mg/kg) or 6 months (0, 10, 40, or 250 mg/kg) weekly by intravenous injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; antibodies unable to interact with genetic material
“No genotoxicity studies of aducanumab were conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity
Not conducted (target absent in wild-type rodents); no proliferative lesions in monkey or Tg2576 studies; FDA agreed
“Carcinogenicity studies of aducanumab were not conducted because its target, aggregated Aβ, is not present in wild-type rodents. No increases in the incidence or severity of proliferative lesions were observed in the 4-week study in monkey or the 13- or 26-week studies in aged Tg2576 mouse.”
Reproductive & developmental
Rat fertility, embryo-fetal and pre/postnatal studies (up to 1000 mg/kg/week IV): no adverse effects; rat of limited relevance
“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”
Safety pharmacology
Incorporated into monkey and Tg2576 toxicity studies; no ECG, CNS or pulmonary effects
“Safety pharmacology was assessed in the pivotal toxicology studies of aducanumab in cynomolgus monkeys and of aducanumab and ch12F6A in aged Tg2576 mice. There were no adverse effects on ECG in the 4-week monkey study or on CNS- or pulmonary-related clinical signs in either species.”
Genotox: Ames
Not conducted (antibody unable to interact with genetic material)
“Genotoxicity studies of aducanumab were not conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vitro mammalian
Not conducted (antibody unable to interact with genetic material)
“Genotoxicity studies of aducanumab were not conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vivo
Not conducted (antibody unable to interact with genetic material)
“Genotoxicity studies of aducanumab were not conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity model
Not conducted; rat and mouse not pharmacologically relevant species
“Carcinogenicity studies of aducanumab were not conducted because rat and mouse are not pharmacologically relevant species.”
Carcinogenicity timing
Not required: Division and Executive Carcinogenicity Assessment Committee agreed to the justification
“The Division and the Executive Carcinogenicity Assessment Committee agreed (September 11, 2015) with the sponsor’s justification for not conducting carcinogenicity studies of aducanumab.”
hERG / QT
No hERG; no adverse ECG effects in 4-week monkey study
“There were no adverse effects on ECG in the 4-week monkey study or on CNS- or pulmonary-related clinical signs in either species.”
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 Aduhelm 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: 13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week (FDA pharmacology/toxicology review, p. 48)
NOAEL / key findings
13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week
“Based on the meningeal vascular inflammation and acute hemorrhage in brain at the MD of 70 mg/kg/week, the NOAEL was the LD of 10 mg/kg/week IV ch12F6A.”
Risksopen answer page →
Immune & cytokine safety
No anti-drug antibodies in the 4-week monkey study
“There were no ADA-positive samples.”
Biodistribution & persistence
TCR: binding to amyloid plaques and cerebral vessel walls; other staining cytoplasmic and clinically irrelevant
“All other staining was cytoplasmic, and, therefore, clinically irrelevant based on the inability of aducanumab to enter cells.”
Modality-specific risk
ARIA-like risk: surrogate exacerbated cerebral amyloid angiopathy (vascular inflammation, thrombosis, hemorrhage) in aged transgenic mice
“resulted in increased incidence and/or severity of meningeal and/or cerebral vascular inflammation, thrombosis, and/or hemorrhage at the mid and high doses consistent with slight exacerbation of the cerebral amyloid angiopathy that increases with aging in this mouse model.”
Anti-drug antibodies: animals
Tg2576 mice: few ADA-positive animals with ~65% lower exposure; impact on study negligible
“Similarly, the two HD ADA-positive ch12F6A-dosed animals showed reductions of ~65% in plasma h12F6A exposure. Based on the small number of animals affected, the impact of ATA on the results of the study was negligible.”
Anti-drug antibodies: patients
Up to 0.6% (15/2689) developed anti-aducanumab antibodies over up to 41 months; neutralizing not assessed
“In up to 41 months of treatment in the combined placebo-controlled and long-term extension periods of Studies 1 and 2, up to 0.6% (15/2689) of patients receiving ADUHELM once monthly developed anti-aducanumab-avwa antibodies.”
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 Aduhelm 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: 13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week (FDA pharmacology/toxicology review, p. 48)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month Tg2576 mouse IV study (aducanumab and murine analog) with 6-week recovery
“BIIB037: A 6 Month Study of BIIB037 by Weekly Intravenous Injection in the Tg2576 Mouse with a 6 Week Recovery Period”
Pivotal GLP studies
Chronic Tg2576 mouse study with murine analog ch12F6A; 4-week monkey and 13-week Tg2576 mouse studies
“toxicity of the murine analog (ch12F6A) was tested in the Tg2576 mouse; shorter-duration toxicity studies were conducted in monkey (4-week) and Tg2576 mouse (13-week).”
DART package
Species: DART
Rat (fertility and early embryonic, embryofetal, pre/postnatal development)
“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”
Reproductive & developmental
Rat fertility, embryo-fetal and pre/postnatal studies (up to 1000 mg/kg/week IV): no adverse effects; rat of limited relevance
“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”
PPND / ePPND: when
PPND in rat (IV): completed before the marketing application, no adverse effects
“There were no adverse effects on fertility and early embryonic development, embryofetal development, or pre- and postnatal development in studies of aducanumab (0, 100, 300, and 1000 mg/kg/week IV) conducted in rat.”
Carcinogenicity
Species: carcinogenicity
Not conducted (target aggregated Aβ absent in wild-type rodents)
“Carcinogenicity studies of aducanumab were not conducted because its target, aggregated Aβ, is not present in wild-type rodents.”
Carcinogenicity model
Not conducted; rat and mouse not pharmacologically relevant species
“Carcinogenicity studies of aducanumab were not conducted because rat and mouse are not pharmacologically relevant species.”
Carcinogenicity timing
Not required: Division and Executive Carcinogenicity Assessment Committee agreed to the justification
“The Division and the Executive Carcinogenicity Assessment Committee agreed (September 11, 2015) with the sponsor’s justification for not conducting carcinogenicity studies of aducanumab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL (high dose) 9x human AUC at 10 mg/kg; ~35x after adjusting QW vs Q4W dosing
“In HD monkeys, plasma exposures (Day 22 AUC0-168 hrs) were 9-fold greater than the expected AUCTAU,SS in humans at the maximum proposed clinical dose of 10 mg/kg IV aducanumab. Adjusting for the differences in dosing frequency (QW in monkey vs. Q4W in human), estimated AUC exposure margins were ~35-fold.”
NOAEL / key findings
13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week
“Based on the meningeal vascular inflammation and acute hemorrhage in brain at the MD of 70 mg/kg/week, the NOAEL was the LD of 10 mg/kg/week IV ch12F6A.”
Efficacy evidenceopen answer page →
Efficacy evidence
Tg2576 transgenic AD mouse with murine analog ch12F6A (plaque and insoluble Aβ reduction)
“In vivo studies in the Tg2576 mouse model were conducted using the murine analog, ch12F6A, a chimeric anti-Aβ monoclonal antibody.”
Why that model
Target is aggregated Aβ, absent in rodents and non-aged monkeys, so transgenic Tg2576 mice were needed
“However, the intended target of aducanumab is aggregated forms of Aβ peptide. Neither rat nor monkey is a particularly relevant species for general toxicity because of the lack of aggregated amyloid in rodent or non-aged monkey.”
Reviewer's view of the efficacy data
FDA: data support that binding Aβ oligomers may reduce their neuronal toxicity, potentially giving acute effects in AD
“The nonclinical information submitted supports the argument that direct interaction of aducanumab with Aβ oligomers may reduce adverse effects of the oligomers on neuronal structure and function, potentially leading to acute treatment effects in patients with Alzheimer’s disease.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No fully relevant standard species; chronic toxicity assessed in Tg2576 transgenic disease-model mouse instead
Why: Target (aggregated amyloid) absent in rodent and non-aged monkey · No relevant species
“Neither rat nor monkey is a particularly relevant species for general toxicity because of the lack of aggregated amyloid in rodent or non-aged monkey.”
“the sponsor was informed that the 6-month study would be sufficient to characterize the chronic toxicity of aducanumab”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic non-oncology indication
Why: Rat and mouse are not pharmacologically relevant species · No relevant species
“Carcinogenicity studies of aducanumab were not conducted because rat and mouse are not pharmacologically relevant species.”
“The Division and the Executive Carcinogenicity Assessment Committee agreed (September 11, 2015) with the sponsor’s justification for not conducting carcinogenicity studies of aducanumab.”
DARTAccepted
Reproductive and developmental toxicity tested only in rat, which is not a pharmacologically relevant species
Why: DART generally not required for Alzheimer's dementia because of the age of the intended population · Within the guideline · Other reason
“Therefore, rat does not appear to be a pharmacologically relevant species. Reproductive and developmental toxicity studies are generally not required by FDA for products indicated for the treatment of patients with dementia of the Alzheimer’s type because of the age of the intended population.”
Similar precedents
KisunlaAntibodies · donanemab · Amyloid-β (N3pG)Monkey + rodent · 22 wkLeqembiAntibodies · lecanemab · Amyloid-β protofibrilsMonkey only · 39 wkAjovyAntibodies · fremanezumab · CGRPMonkey + rodent · 26 wkAmvuttraOligos · vutrisiran · TTR (siRNA)Monkey + rodent · 40 wkAndembryAntibodies · garadacimab · Factor XIIaMonkey + rodent · 26 wkCinqairAntibodies · reslizumab · IL-5Monkey + rodent · 26 wk