Kisunla
donanemab
Species
MonkeyMouse
Longest study
22 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey and PDAPP transgenic mouse (surrogate antibody)
“toxicity studies were conducted in cynomolgus monkey (6-week IV donanemab) to assess for any off-target toxicity, and in the PDAPP transgenic mouse model (6-week and 6-month SC mE8c, a murine surrogate) to assess for relevant on-target effects”
Why that species
Not pharmacologically active in normal animals; monkey for off-target toxicity, amyloid-bearing PDAPP mice for on-target effects
“Donanemab is not pharmacologically active in normal rodent or nonrodent; therefore, toxicity studies were conducted in cynomolgus monkey (6-week IV donanemab) to assess for any off-target toxicity”
Surrogate molecule
Yes: murine analog mE8c, used for repeat-dose toxicity studies in PDAPP transgenic mice
“These studies used mE8c, the murine analog of donanemab, to avoid immunogenicity that would be expected with donanemab, a humanized antibody, in mouse.”
Study lengthopen answer page →
Longest pivotal study
22 weeks
“The dosing period was approximately 5 months.”
Pivotal GLP studies
GLP monkey 6-week weekly IV; GLP PDAPP mouse (mE8c) 6-week and ~5-month weekly SC
“In the pivotal (GLP) studies, mE8c was administered to 12- to 15-month-old PDAPP mice weekly for 6 weeks (0, 10, 30, or 100 mg/kg SC) or 5 months (0, 30, or 100 mg/kg SC).”
Route in tox
IV (monkey); SC (mouse surrogate)
“Cynomolgus monkey: in the 6-week (GLP-compliant) IV toxicity study (with 3-month recovery), donanemab was administered by IV injection at doses of 0, 1, 10, and 100 mg/kg QW.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; antibodies unable to interact with genetic material
“No genotoxicity studies of donanemab were conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity
Not conducted; target absent in wild-type rodents; FDA waived after carcinogenicity assessment
“Carcinogenicity studies of donanemab were not conducted because its target, human AβN3pE-x peptide, is not present in wild-type rodents, and carcinogenicity studies in transgenic rodents are not feasible.”
Reproductive & developmental
Not conducted; not required given age of Alzheimer's population
“Developmental and reproductive toxicity studies were not conducted based on the age of the indicated population.”
Safety pharmacology
Incorporated into 6-week monkey study; no effects on body temperature, cardiovascular, neurological or respiratory function
“Safety pharmacology was assessed in the 6-week toxicity study of donanemab in cynomolgus monkey. There were no donanemab-related effects on body temperature, cardiovascular function, neurological examinations, or respiratory function.”
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 Kisunla 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: No drug-related adverse effects: monkey at 100 mg/kg/week IV for 6 weeks; PDAPP mice (mE8c) at 100 mg/kg/week SC for 5 months (FDA pharmacology/toxicology review, p. 20)
NOAEL / key findings
No drug-related adverse effects: monkey at 100 mg/kg/week IV for 6 weeks; PDAPP mice (mE8c) at 100 mg/kg/week SC for 5 months
“In summary, there were no drug-related adverse effects in aged PDAPP mice administered mE8c at 100 mg/kg/week SC for 5 months, or in cynomolgus monkeys administered donanemab for 6 weeks at 100 mg/kg/week IV.”
Risksopen answer page →
Immune & cytokine safety
ADA in 1/6 low, 1/6 mid, 4/12 high-dose monkeys (1/12 controls); reduced exposure only in 2 high-titer recovery animals
“Anti-drug antibodies (ADA) were present in samples from 1/12 control, 1/6 LD, 1/6 MD, and 4/12 HD animals; donanemab concentrations in serum were only affected by ADA in the 2 HD recovery animals with the highest titers”
Biodistribution & persistence
TCR in human and monkey tissues: only cytoplasmic/nuclear binding, considered toxicologically irrelevant
“Tissue cross-reactivity studies conducted in a panel of normal human and cynomolgus monkey tissues demonstrated specific binding of donanemab that was exclusively cytoplasmic and/or nuclear, and, therefore, toxicologically irrelevant”
Modality-specific risk
ARIA/microhemorrhage from plaque removal; surrogate did not worsen microhemorrhage in aged PDAPP mice, but ARIA seen clinically
“These results suggest that the removal of amyloid plaques is not associated with exacerbation of CAA-related microhaemorrhage in aged PDAPP mice up to three months of dosing. In contrast, amyloid-related imaging abnormalities (ARIAs) were observed in clinical studies with donanemab.”
Similar precedents
Leqembilecanemab · Amyloid-β protofibrilsMonkey only · 39 wkAduhelmaducanumab · Aggregated amyloid-βMonkey + rodent · 26 wkAjovyfremanezumab · CGRPMonkey + rodent · 26 wkEmgalitygalcanezumab · CGRPMonkey + rodent · 26 wkVyeptieptinezumab · CGRPMonkey + rodent · 26 wkAimovigerenumab · CGRP receptorMonkey only · 26 wk