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”
Species: general tox
Rat (13-week) and cynomolgus monkey (26-week)
“All studies were previously reviewed, and the results of pivotal 13-week rat and 26-week monkey studies are summarized below.”
Species: DART
Rat (female fertility/pre- and postnatal, EFD), rabbit (EFD, male fertility) and monkey fertility endpoints in 26-week study
“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, and a male fertility and paternally-mediated EFD study in male rabbits.”
Species: carcinogenicity
Not conducted (weight-of-evidence assessment accepted)
“No in vivo animal carcinogenicity studies were requested by the Division after consulting with CDER’s Executive Carcinogenicity Assessment Committee (April 18, 2017) and the sponsor’s carcinogenicity assessment is considered adequate.”
Surrogate used in
No surrogate used; evinacumab 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.”
Genotox: Ames
Not conducted (ICH S6; not expected to interact with DNA)
“Evinacumab is not expected to interact directly with DNA and mutagenicity studies are not appropriate for this reason.”
Genotox: in vitro mammalian
Not conducted (ICH S6; not expected to interact with DNA)
“Evinacumab is not expected to interact directly with DNA and mutagenicity studies are not appropriate for this reason.”
Genotox: in vivo
Not conducted (ICH S6; not expected to interact with DNA)
“Evinacumab is not expected to interact directly with DNA and mutagenicity studies are not appropriate for this reason.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment from literature and animal toxicology studies
“The Applicant submitted a weight of evidence assessment to address the carcinogenic potential of evinacumab, which was based on information available from relevant literature and animal toxicology studies completed under the IND.”
Carcinogenicity timing
Not required: no animal studies requested after Executive CAC consultation
“No in vivo animal carcinogenicity studies were requested by the Division after consulting with CDER’s Executive Carcinogenicity Assessment Committee (April 18, 2017) and the sponsor’s carcinogenicity assessment is considered adequate.”
hERG / QT
No hERG assay; no heart rate, blood pressure or ECG effects in rats and monkeys up to 100 mg/kg/week
“Administration of evinacumab at up to 100 mg/kg/week (SC or IV) for 5 and 26 consecutive weeks (in rats and monkeys, respectively), did not result in any test article-related cardiovascular (heart rate, blood pressure, and electrocardiography), respiratory (breaths/minute and pulse oximetry), or CNS (neurobehavioral observation battery) effects.”
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
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/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)”
Anti-drug antibodies: animals
ADA low in rats (5-28%) and monkeys (up to 42%, mainly low doses); rabbits highly immunogenic (16-100%)
“Antidrug antibodies (ADA) responses were generally low in rats (5 to 28%) and monkeys (up to 42%, but primarily at lower doses), but evinacumab was highly immunogenic in rabbits (16 to 100%)”
Anti-drug antibodies: patients
No apparent ADA response in phase 3 clinical studies
“The absence of any apparent ADA response in the Applicant’s phase 3 clinical studies is noted.”
Label warnings
- Serious Hypersensitivity Reactions
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, 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 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
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/week IV in rats and monkeys (chronic studies) (FDA pharmacology/toxicology review, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (SC/IV) study with 13-week recovery
“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.”
DART package
Species: DART
Rat (female fertility/pre- and postnatal, EFD), rabbit (EFD, male fertility) and monkey fertility endpoints in 26-week study
“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, and a male fertility and paternally-mediated EFD study in male rabbits.”
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”
PPND / ePPND: when
Combined female fertility/early embryonic/PPND study in rat completed before the marketing application
“In rats, a combined female fertility and early embryonic development (to implantation) and pre and postnatal developmental study was conducted to assess the effects of evinacumab at doses of 30 and 100 mg/kg administered subcutaneously every three days (Q3D) to females from 2 weeks premating through gestation”
Carcinogenicity
Species: carcinogenicity
Not conducted (weight-of-evidence assessment accepted)
“No in vivo animal carcinogenicity studies were requested by the Division after consulting with CDER’s Executive Carcinogenicity Assessment Committee (April 18, 2017) and the sponsor’s carcinogenicity assessment is considered adequate.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment from literature and animal toxicology studies
“The Applicant submitted a weight of evidence assessment to address the carcinogenic potential of evinacumab, which was based on information available from relevant literature and animal toxicology studies completed under the IND.”
Carcinogenicity timing
Not required: no animal studies requested after Executive CAC consultation
“No in vivo animal carcinogenicity studies were requested by the Division after consulting with CDER’s Executive Carcinogenicity Assessment Committee (April 18, 2017) and the sponsor’s carcinogenicity assessment is considered adequate.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL 100 mg/kg/week IV: ~1x (rat) and 4x (monkey) MRHD AUC at 15 mg/kg IV every 4 weeks
“The NOAELs for chronic administration of evinacumab in rats and monkeys were 100 mg/kg/week IV for both species, or ~1 and 4-fold, respectively, the maximum recommended human dose (MRHD) of 15 mg/kg IV every 4 weeks based on AUC)”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Evinacumab in hyperlipidemic mouse models (ApoE-/-, Ldlr-/-, db/db, high-fat diet) and normolipidemic mice
“Evidence of pharmacodynamic activity of evinacumab was established following single and multiple dose (8 week) SC administration in normolipidemic (C57BL/6) and multiple hyperlipidemic (ApoE-/- , Ldlr-/- , db/db and high-fat diet fed) mouse models”
Why that model
Evinacumab binds human, mouse, rat and monkey ANGPTL3 with high affinity (KD 0.3-1.3 nM)
“In vitro, evinacumab binds the N-terminal domain of ANGPTL3 proteins containing LPL binding regions from humans, mice, rats, and monkeys with high affinity (sub to low-nanomolar KD values ranging from 0.3 to 1.3 nM).”
Reviewer's view of the efficacy data
FDA: TG and HDL-C pathways well characterized; exact mechanism of LDL-C lowering less clear
“While the pathways contributing to TG and HDL-C reduction with ANGPTL3 inactivation are well characterized, the exact mechanism responsible for evinacumab-mediated LDL-C lowering is less clear.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No in vivo carcinogenicity studies; weight-of-evidence assessment from literature and toxicology studies
Why: Executive Carcinogenicity Assessment Committee consulted; no animal studies requested and sponsor's assessment adequate · Weight of evidence
“The Applicant submitted a weight of evidence assessment to address the carcinogenic potential of evinacumab, which was based on information available from relevant literature and animal toxicology studies completed under the IND.”
“No in vivo animal carcinogenicity studies were requested by the Division after consulting with CDER’s Executive Carcinogenicity Assessment Committee (April 18, 2017) and the sponsor’s carcinogenicity assessment is considered adequate.”
Safety marginAccepted with a conditionBeyond the letter
Rabbit fetal malformations (internal hydrocephaly, flexed paws) at exposures below clinical; no margin, mechanism unknown
Why: Unknown mechanism, severity and low exposure margins mean a potential human risk; addressed in Warning and Precaution labeling
“These fetal malformations occur at doses that resulted in less than the clinical exposure.”
“Therefore, we recommend that the embryo-fetal toxicity signal in rabbits be included in the Warning and Precaution section of product labeling.”
Safety marginVerdict not stated
Rat chronic SC NOAEL gives 0.4-fold the MRHD exposure (no margin)
“100 mg/kg/week in both species by the SC route (0.4 and 3-fold the MRHD in rats and monkeys, respectively, based on AUC).”
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