Leqembi
lecanemab
Species
Monkey
Longest study
39 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 only
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Why that species
Cynomolgus IgG1 sequence similar to human IgG1; monkeys predictive of antibody pharmacokinetics
“Cynomolgus monkey IgG1 has a similar sequence to human IgG1 and cynomolgus monkeys were considered generally predictive of the pharmacokinetics of such antibodies in humans.”
Surrogate molecule
Yes: rodent surrogate mAb158, used for microhemorrhage studies in mice because lecanemab induces anti-drug antibodies in rodents
“Given the production of anti-drug antibodies against lecanemab in rodents, microhemorrhage studies were conducted with the rodent surrogate, mAb158.”
Species: general tox
Cynomolgus monkey only (4- and 39-week studies)
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Species: DART
Not conducted, because of the age of the intended patient population
“Reproductive and developmental toxicology studies were not conducted for lecanemab because of the age of the intended patient population.”
Species: carcinogenicity
Not conducted; no pharmacological activity in mouse or rat
“Carcinogenicity studies were not conducted because of the lack of pharmacological activity in rodent species (mouse, rat), making standard carcinogenicity studies infeasible.”
Surrogate used in
Yes: rodent surrogate mAb158 (lecanemab immunogenic in rodents), incl. microhemorrhage studies in mice
“Given the production of anti-drug antibodies against lecanemab in rodents, microhemorrhage studies were conducted with the rodent surrogate, mAb158.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In the 39-week study (0, 15, 50, and 100 mg/kg/week) (with 2-week recovery)”
Pivotal GLP studies
4-week and 39-week cynomolgus monkey studies
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey”
Route in tox
Intravenous bolus, weekly
“In both studies, lecanemab was administered weekly by intravenous bolus injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Studies evaluating genotoxicity of biotechnology products, are not mandatory in accordance with ICH S6 guideline”
Carcinogenicity
Not conducted; not necessary because of neutralizing anti-drug antibodies in rodents to lecanemab and its surrogate mAb158
“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”
Reproductive & developmental
Not conducted; reproductive and developmental toxicology studies not required
“No reproductive and developmental toxicology studies were conducted with lecanemab. The sponsor was informed on November 6, 2012, that reproductive and development toxicology studies are not required”
Safety pharmacology
No stand-alone safety pharmacology studies (ICH S6(R1) and S7A)
“In accordance with ICH guidelines S6(R1) and S7A no stand-alone safety pharmacology studies were performed.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted because monoclonal antibodies are not expected to interact directly with DNA.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted because monoclonal antibodies are not expected to interact directly with DNA.”
Genotox: in vivo
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted because monoclonal antibodies are not expected to interact directly with DNA.”
Carcinogenicity model
Not conducted; standard rodent studies infeasible (no pharmacological activity in mouse or rat)
“Carcinogenicity studies were not conducted because of the lack of pharmacological activity in rodent species (mouse, rat), making standard carcinogenicity studies infeasible.”
Carcinogenicity timing
Not required (FDA agreement, 2014)
“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”
hERG / QT
No hERG assay; no adverse cardiovascular, respiratory or CNS effects in the 4-week monkey study
“The core battery of safety pharmacology assessments was conducted in the 4-week pivotal study conducted in monkey. There were no adverse effects on cardiovascular, respiratory, or CNS 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 Leqembi 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: NOAEL 100 mg/kg once weekly in the 39-week study (EMA assessment report, p. 31)
NOAEL / key findings
NOAEL 100 mg/kg once weekly in the 39-week study
“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period, NOAEL (be 100 mg/kg, once a week) corresponded to mean AUC(0-384h) for males and females of”
Risksopen answer page →
Immune & cytokine safety
No ADAs detected in monkey IV repeat-dose and SC local irritation studies
“No ADAs to lecanemab were detected in the serum samples from i.v. repeat-dose toxicity and s.c. local irritation studies in cynomolgus monkeys.”
Biodistribution & persistence
CSF-to-plasma ratios 0.53, 0.44 and 0.30% at 1, 5 and 15 mg/kg (AUC-based)
“CSF-to-plasma ratios were 0.53, 0.44 and 0.30% at 1, 5 and 15 mg/kg based on AUC0-168h, respectively.”
Modality-specific risk
Cerebral microhemorrhage; high binding to human FcγRI and FcγRIII may contribute
“Lecanemab also demonstrated high binding affinity for human FcγRs (FcγRI and FcγRIII), which is thought be involved in amyloid beta clearance but may also contribute to cerebral microhemorrhage.”
Anti-drug antibodies: animals
No anti-lecanemab antibodies detected in the 39-week monkey study
“Toxicokinetics: No anti-lecanemab antibodies were detected throughout the study.”
Anti-drug antibodies: patients
3.4% treatment-emergent ADA (IV, 18 months); 1.9% neutralizing
“During the 18-month treatment period in Study 2, 3.4% (30/883) of patients treated with LEQEMBI 10 mg/kg every two weeks developed treatment-emergent anti-lecanemab-irmb antibodies, and 1.9% (17/885) developed neutralizing antibodies.”
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 Leqembi 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: NOAEL 100 mg/kg once weekly in the 39-week study (EMA assessment report, p. 31)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (weekly IV) GLP study with 13-week recovery
“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period”
Pivotal GLP studies
4-week and 39-week cynomolgus monkey studies
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey”
DART package
Species: DART
Not conducted, because of the age of the intended patient population
“Reproductive and developmental toxicology studies were not conducted for lecanemab because of the age of the intended patient population.”
Reproductive & developmental
Not conducted; reproductive and developmental toxicology studies not required
“No reproductive and developmental toxicology studies were conducted with lecanemab. The sponsor was informed on November 6, 2012, that reproductive and development toxicology studies are not required”
PPND / ePPND: when
Not conducted: not required given the age of the intended patient population
“Reproductive and developmental toxicology studies were not conducted for lecanemab because of the age of the intended patient population.”
Carcinogenicity
Species: carcinogenicity
Not conducted; no pharmacological activity in mouse or rat
“Carcinogenicity studies were not conducted because of the lack of pharmacological activity in rodent species (mouse, rat), making standard carcinogenicity studies infeasible.”
Carcinogenicity model
Not conducted; standard rodent studies infeasible (no pharmacological activity in mouse or rat)
“Carcinogenicity studies were not conducted because of the lack of pharmacological activity in rodent species (mouse, rat), making standard carcinogenicity studies infeasible.”
Carcinogenicity timing
Not required (FDA agreement, 2014)
“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL (39-week, weekly dosing): 27-fold (AUC) and 14-fold (Cmax) human exposure
“Once weekly dosing resulted in safety margin levels of 27/14-fold (AUC/Cmax)”
NOAEL / key findings
NOAEL 100 mg/kg once weekly in the 39-week study
“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period, NOAEL (be 100 mg/kg, once a week) corresponded to mean AUC(0-384h) for males and females of”
Efficacy evidenceopen answer page →
Efficacy evidence
Tg2576 and APPArcSwe Alzheimer's mice with murine analog mAb158; lecanemab tested in vitro
“Therefore, a series of in vivo studies were performed to assess the ability of the murine analog, mAb158, to alter the levels of Aβ protofibrils in the brains of two mouse models of Alzheimer’s disease (Tg2576 and APPArcSwe).”
Why that model
Lecanemab is immunogenic in mice, so transgenic-model pharmacodynamic studies used the murine analog
“In vivo studies in transgenic animal models to characterize the pharmacodynamic effects of lecanemab were not conducted because of immunogenicity.”
Reviewer's view of the efficacy data
FDA: in vitro and in vivo pharmacology support the proposed mechanism of action labeling
“The results of the primary pharmacology in vitro and in vivo studies support the description of the mechanism of action in the Indications and Usage, Description (Section 11), and Mechanism of Action (Section 12.1) sections of the applicant’s proposed labeling.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No rodent carcinogenicity studies for long-term use; weight-of-evidence carcinogenicity risk assessment instead
Why: Option afforded by ICH S6 and S1; neutralizing anti-drug antibodies in rodents to lecanemab and its mouse surrogate · Within the guideline · Weight of evidence · No relevant species
“A weight-of-evidence assessment of carcinogenicity risk was conducted considering this possibility afforded by ICH S6 and S1 guidelines instead of conducting 2-years carcinogenicity study in rodents and 6-month Tg Ras study to support long-term human use of lecanemab. The whole approach is supported.”
“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Patients aged 50 years and older; target soluble Aβ aggregates not detectable in standard reproductive toxicology species · Weight of evidence · No relevant species
“This was justified by the applicant according to a weight of evidence approach considering notably that the age of the intended patient population (50 years of age and older). In addition, it was pointed out that standard preclinical models used for the conduct of reproductive and developmental studies are not relevant since the soluble aggregates of Aβ targeted by lecanemab are not detectable in these species.”
“At the End of Phase 2 meeting (IND 105081, November 6, 2012), the applicant was informed that reproductive and development toxicology studies would not be required to support an application because of the age of the patient population”
SpeciesAcceptedBeyond the letter
On-target cerebral microhaemorrhage risk assessed only in non-GLP pharmacology studies in transgenic mice with the murine surrogate mAb158
Why: On-target microhaemorrhage evaluable only in transgenic mice with the surrogate; FDA later no longer required the assessment · No relevant species
“The particularity of the toxicological programme is on-target toxicity evaluation of cerebral microhaemorrhage potential can be conducted only as part of the non-GLP repeated-dose pharmacology studies in transgenic mice (Tg2576 and Tg-APPArcSwe) using the murine monoclonal antibody surrogate.”
“In a letter from the Division dated July 2, 2014, the applicant was informed that a nonclinical assessment of the potential for lecanemab to cause microhemorrhage would no longer be required.”
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