Evkeeza
evinacumab
Species
MonkeyRatRabbit
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, rat and rabbit
“The toxicology profile of evinacumab was evaluated in rats, monkeys and rabbits, which are pharmacologically relevant nonclinical species”
Why that species
High sequence homology (83-98%) to human ANGPTL3 and evinacumab target binding in monkey, rabbit and rat
“The cynomolgus monkey, rabbit, and rat are pharmacologically relevant species for toxicologic evaluation of evinacumab considering the high sequence homology (83-98%) to human ANGPTL3 and evinacumab target binding data”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats, monkeys and rabbits
“The toxicology profile of evinacumab was evaluated in rats, monkeys and rabbits, which are pharmacologically relevant nonclinical species”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Evinacumab was administered once-weekly to sexually mature male and female cynomolgus monkeys (4 to 8 years old) for 26 weeks via SC injection at 10, 30, or 100 mg/kg/week or IV injection at 100 mg/kg/week, followed by a 13-week recovery.”
Pivotal GLP studies
Pivotal 13-week rat and 26-week cynomolgus monkey studies
“All studies were previously reviewed, and the results of pivotal 13-week rat and 26-week monkey studies are summarized below.”
Route in tox
Subcutaneous and intravenous
“Evinacumab was administered once-weekly to sexually mature male and female cynomolgus monkeys (4 to 8 years old) for 26 weeks via SC injection at 10, 30, or 100 mg/kg/week or IV injection at 100 mg/kg/week, followed by a 13-week recovery.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“no genotoxicity studies were performed with evinacumab, per ICH S6.”
Carcinogenicity
Not conducted; weight-of-evidence assessment (literature and animal toxicology studies) found no identified carcinogenicity risk
“The Applicant submitted a weight of evidence carcinogenicity assessment for evinacumab based on available evidence from relevant literature and completed animal toxicology studies, which suggested that there is no identified risk of carcinogenicity for evinacumab.”
Reproductive & developmental
Fertility endpoints in 26-week monkey study; rat combined female fertility/early embryonic/pre- and postnatal study; rat and rabbit EFD studies
“The reproductive toxicity of evinacumab was assessed using male and female fertility endpoints collected from the chronic 26-week monkey toxicity study, and by conducting combined female fertility/early embryonic/pre and postnatal development study in rats, embryofetal development studies in rats and rabbits”
Safety pharmacology
Integrated into pivotal GLP repeat-dose rat and monkey studies
“Safety pharmacology studies were integrated into pivotal GLP repeat dose toxicology studies of evinacumab conducted in rats and cynomolgus monkeys.”
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 Evkeeza 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: NOAEL 100 mg/kg/week IV in rats and monkeys (chronic studies) (FDA pharmacology/toxicology review, p. 8)
NOAEL / key findings
NOAEL 100 mg/kg/week IV in rats and monkeys (chronic studies)
“The NOAELs for chronic administration of evinacumab in rats and monkeys were 100 mg/kg/week IV for both species”
Risksopen answer page →
Immune & cytokine safety
Low ADA responses in rats and monkeys; highly immunogenic in rabbits
“Anti-drug antibody (ADA) responses were generally low in rats and monkeys, but evinacumab was highly immunogenic in rabbits.”
Biodistribution & persistence
Crosses the placenta in rats (fetal to maternal concentration ratio 0.42-0.65)
“Evinacumab crossed the placenta in rats, with mean fetal to maternal concentration ratios ranging from 0.42 to 0.65”
Modality-specific risk
Embryo-fetal toxicity: rabbit fetal malformations (domed head, hydrocephalus, flexed limbs) below the MRHD
“evinacumab-dgnb to pregnant rabbits during the period of organogenesis resulted in fetal malformations (domed head, hydrocephalus and flexed limbs) at doses below the maximum recommended human dose (MRHD)”
Similar precedents
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