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.”
Species: general tox
Cynomolgus monkey (donanemab, 6-week IV) and aged PDAPP transgenic mouse (murine surrogate mE8c)
“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”
Species: DART
Not conducted (age of indicated population)
“Developmental and reproductive toxicity studies were not conducted based on the age of the indicated population.”
Species: carcinogenicity
Not conducted: target absent in wild-type rodents; transgenic rodent studies not feasible
“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.”
Surrogate used in
Yes: murine analog mE8c in aged PDAPP mice for 6-week and 5-month toxicity studies
“These studies used mE8c, the murine analog of donanemab, to avoid immunogenicity that would be expected with donanemab, a humanized antibody, in mouse. 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).”
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.”
Genotox: Ames
Not conducted (antibodies do not interact with genetic material)
“No genotoxicity studies of donanemab were conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vitro mammalian
Not conducted (antibodies do not interact with genetic material)
“No genotoxicity studies of donanemab were conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vivo
Not conducted (antibodies do not interact with genetic material)
“No genotoxicity studies of donanemab were conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity model
Not conducted: no pharmacologically relevant rodent species
“Carcinogenicity studies of donanemab were not conducted because wild-type rat and mouse are not pharmacologically relevant species.”
Carcinogenicity timing
Not required: FDA informed sponsor carcinogenicity studies not needed for BLA
“Following review of an initial carcinogenicity assessment, the sponsor was informed that carcinogenicity studies of donanemab would not be required to support a BLA”
hERG / QT
No hERG assay; no effects on cardiovascular, neurological or respiratory function in 6-week monkey study
“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
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: 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.”
Anti-drug antibodies: animals
Monkey ADA in 1/6 low, 1/6 mid, 4/12 high-dose (1/12 controls); exposure reduced 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”
Anti-drug antibodies: patients
88.1% treatment-emergent ADA; all ADA-positive patients had neutralizing antibodies
“A total of 88.1 % donanemab-treated patients tested positive for treatment-emergent anti-drug antibodies (ADA) and all of the patients with ADA had neutralizing antibodies (NAb).”
Label warnings
Boxed warning: Amyloid related imaging abnormalities
- Amyloid Related Imaging Abnormalities
- Hypersensitivity Reactions
- Infusion-Related Reactions
NeurotoxicityHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and 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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month SC studies in PDAPP mice with murine surrogate mE8c (non-GLP study, plus a GLP study ended early); no recovery phase stated
“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)”
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).”
DART package
Species: DART
Not conducted (age of indicated population)
“Developmental and reproductive toxicity studies were not conducted based on the age of the indicated population.”
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.”
PPND / ePPND: when
Not conducted: not required given the age of the Alzheimer's population
“Developmental and reproductive toxicity studies were not conducted based on the age of the indicated population.”
Carcinogenicity
Species: carcinogenicity
Not conducted: target absent in wild-type rodents; transgenic rodent studies not feasible
“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.”
Carcinogenicity model
Not conducted: no pharmacologically relevant rodent species
“Carcinogenicity studies of donanemab were not conducted because wild-type rat and mouse are not pharmacologically relevant species.”
Carcinogenicity timing
Not required: FDA informed sponsor carcinogenicity studies not needed for BLA
“Following review of an initial carcinogenicity assessment, the sponsor was informed that carcinogenicity studies of donanemab would not be required to support a BLA”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey high dose (no adverse effects) ~10x human AUC at 1400 mg/month, adjusted for dosing frequency
“maximum proposed clinical dose of 1400 mg/month IV donanemab. Adjusting for the differences in dosing frequency (weekly in monkey vs. every 4 weeks in human), the estimated AUC exposure margin was ~10-fold.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Aged PDAPP transgenic mice (amyloid plaques) treated with murine surrogate mE8c: dose- and effector-dependent plaque reduction
“Donanemab binds to N3pE containing amyloid beta plaques, which were demonstrated to be reduced via typical antibody clearance mechanisms in aged PDAPP mice treated with murine surrogate mE8c in a dose-and effector-function dependent manner.”
Why that model
Donanemab not pharmacologically active in normal rodents or nonrodents; on-target effects studied in PDAPP mice with murine surrogate mE8c
“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, and in the PDAPP transgenic mouse model (6-week and 6-month SC mE8c, a murine surrogate) to assess for relevant on-target effects”
Reviewer's view of the efficacy data
EMA: proof of concept sufficiently demonstrated via surrogate plaque clearance in aged PDAPP mice
“Overall, the proof of concept has been sufficiently demonstrated.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically active species; off-target toxicity in monkeys (6-week only) and on-target effects with a murine surrogate in transgenic PDAPP mice
Why: Donanemab not pharmacologically active in normal rodents or nonrodents · No relevant species
“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, and in the PDAPP transgenic mouse model (6-week and 6- month SC mE8c, a murine surrogate) to assess for relevant on-target effects (toxicity and pharmacology).”
Study lengthAcceptedBeyond the letter
GLP six-month surrogate study in aged PDAPP mice terminated early, giving about five months of dosing
Why: Early termination due to age-related mortality in aged transgenic mice · Other reason
“groups were terminated early due to age-related mortality (primarily associated with lymphoma and murine progressive cardiomyopathy) on Day 140/141 (F) or Day 151/152 (M). The dosing period was approximately 5 months.”
“The NOAEL was the HD. Determination of m2Ec plasma concentrations at the end of the dosing period confirmed systemic exposure at both doses. The study was adequately conducted.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for long-term therapy; weight-of-evidence assessment instead
Why: Target absent in wild-type rodents; transgenic rodent studies not feasible · No relevant species · Weight of evidence
“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.”
“Following review of an initial carcinogenicity assessment, the sponsor was informed that carcinogenicity studies of donanemab would not be required to support a BLA (see July 20, 2020, Type C Meeting Written Responses, and review by Dr. Hawver, February 4, 2021).”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Age of the Alzheimer’s disease population · Other reason
“The sponsor was informed that reproductive and developmental toxicology studies are generally not required to support clinical development or marketing approval for products intended for the treatment of Alzheimer’s disease, based on the age of the population with that condition”
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