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.”
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.”
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 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: 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.”