Praluent
alirocumab
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The Applicant identified the rat and monkey as pharmacologically relevant species for toxicology testing with alirocumab; both species express PCSK9, to which alirocumab binds with high affinity.”
Why that species
Both species express PCSK9 bound with high affinity; human and monkey PCSK9 bound with comparable affinity, rodent PCSK9 with lower affinity
“Alirocumab was shown to bind human and Cynomolgus monkey PCSK 9 with comparable affinity and lower affinity, but in nanomolar range to mouse, hamster, and rat PCSK9.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats and cynomolgus monkeys
“Repeat dose toxicity studies were conducted in rats and Cynomolgus monkeys.”
Species: general tox
Rat and cynomolgus monkey
“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”
Species: DART
Rat (EFD) and cynomolgus monkey (enhanced PPND)
“Reproductive toxicity assessments were conducted in rats during the period of embryofetal development at up to 24-fold and in monkeys in an enhanced pre/postnatal development toxicity study at up to 81-fold the 150 mg Q2W human dose, based on plasma exposure.”
Species: carcinogenicity
Not conducted (waived on weight of evidence)
“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”
Surrogate used in
No surrogate used; clinical antibody tested in rats and cynomolgus monkeys
“The Applicant identified the rat and monkey as pharmacologically relevant species for toxicology testing with alirocumab; both species express PCSK9, to which alirocumab binds with high affinity.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”
Pivotal GLP studies
Rat and monkey studies up to 6 months, weekly SC and IV dosing
“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”
Route in tox
SC and IV (weekly)
“Route of administration Groups 2-4, subcutaneous: 5, 15, and 75 mg/kg/week Group 5, intravenous infusion (~30 min): 50 mg/kg/week only”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6); not expected to interact with DNA
“Alirocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, in accordance with ICH-S6.”
Carcinogenicity
Waived on weight of evidence (ICH S6); no preneoplastic or neoplastic lesions in 6-month studies
“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”
Reproductive & developmental
Rat EFD: no developmental effects, maternal deaths at high dose; monkey ePPND: no teratogenicity; no fertility effects in 6-month monkey study
“Reproductive and developmental toxicity studies were conducted in rats and monkeys; no teratogenic effects were observed at exposure margins of 12-fold and 81-fold, respectively. Alirocumab did not produce any effect on fertility parameters evaluated as part of the 6-month toxicity study in monkeys.”
Safety pharmacology
Integrated into rat and monkey toxicity studies; no cardiovascular or respiratory effects
“Safety pharmacology endpoints were integrated in toxicology studies in both rats and Cynomolgus monkeys. There were no adverse effects of alirocumab on cardiovascular function in monkeys”
Genotox: Ames
Not conducted (ICH S6)
“Alirocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, in accordance with ICH-S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Alirocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, in accordance with ICH-S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Alirocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, in accordance with ICH-S6.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment, no preneoplastic or neoplastic lesions in rats or monkeys up to 6 months
“No preneoplastic or neoplastic lesions were observed that could be associated with alirocumab administration in rats or monkeys at up to 6 months duration. Based on a weight of evidence approach as outlined in the ICH-S6 guidance and discussed in detail in Section 8 of this review, alirocumab was not tested in an animal model for carcinogenesis.”
Carcinogenicity timing
Not required: waiver granted on weight of evidence (ICH S6)
“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”
hERG / QT
No hERG assay; no adverse cardiovascular effects in monkey toxicity studies
“Safety pharmacology endpoints were integrated in toxicology studies in both rats and Cynomolgus monkeys. There were no adverse effects of alirocumab on cardiovascular function in monkeys, and there was no physical or anatomic evidence of cardiovascular or respiratory effects in monkey or rats.”
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 Praluent 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 at highest doses in 6-month studies (rat 50, monkey 75 mg/kg/week SC); no dose-limiting toxicity (FDA pharmacology/toxicology review, p. 144)
NOAEL / key findings
NOAEL at highest doses in 6-month studies (rat 50, monkey 75 mg/kg/week SC); no dose-limiting toxicity
“Alirocumab was subcutaneously administered for 6 months to rats at up to 50 mg/kg/week and to monkeys at up to 75 mg/kg/week; no evidence of dose-limiting test item-related toxicity was observed”
Risksopen answer page →
Immune & cytokine safety
Low anti-drug antibody incidence; neutralizing antibodies low in rats and negligible in monkeys
“Incidences of neutralizing antibodies were low in rats and negligible in monkeys.”
Biodistribution & persistence
Crosses placenta: infant monkey serum levels at birth comparable to maternal
“Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier.”
Modality-specific risk
Suppressed humoral immunity (TDAR) in infant monkeys exposed in utero; exaggerated lipid-lowering pharmacology
“dose-related decreases in T-cell dependent antibody response (predominantly IgG) to a known antigen (KLH) were observed in infant monkeys exposed to alirocumab in utero, which indicated suppression of adaptive immunity.”
Anti-drug antibodies: animals
Low ADA incidence (slightly higher in rats than monkeys); reduced exposure in ADA-positive animals did not affect interpretation
“In animals positive for anti-drug antibodies, serum alirocumab concentrations could be reduced. However, because the incidence of ADA was generally low, this did not influence the overall interpretation of the study. Rat appeared to have a slightly increased incidence of ADA compared to Cynomolgus monkey.”
Anti-drug antibodies: patients
5.5% (504/9,091) ADA in Trial 1; neutralizing 0.5% (43/9,091)
“In adult patients with CV disease (Trial 1), the incidence of anti-alirocumab antibody (ADA) formation was 5.5% (504/9,091) in patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks for up to 5 years (with a median treatment exposure of 31 months). Neutralizing antibody (NAb) responses were observed in 0.5% (43/9,091) of all patients treated with PRALUENT.”
Label warnings
- Hypersensitivity Reactions
Hypersensitivity & infusion reactions
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 Praluent 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 at highest doses in 6-month studies (rat 50, monkey 75 mg/kg/week SC); no dose-limiting toxicity (FDA pharmacology/toxicology review, p. 144)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey study (SC and IV, once weekly) with 13-week recovery
“Table 8: Study design for a 26-week intravenous and subcutaneous toxicity study with alirocumab in cynomolgus monkeys with a 13-week recovery period”
Pivotal GLP studies
Rat and monkey studies up to 6 months, weekly SC and IV dosing
“The primary nonclinical toxicity studies of alirocumab were conducted in rats and monkeys for up to 6 months duration with weekly subcutaneous and intravenous dosing.”
DART package
Species: DART
Rat (EFD) and cynomolgus monkey (enhanced PPND)
“Reproductive toxicity assessments were conducted in rats during the period of embryofetal development at up to 24-fold and in monkeys in an enhanced pre/postnatal development toxicity study at up to 81-fold the 150 mg Q2W human dose, based on plasma exposure.”
Reproductive & developmental
Rat EFD: no developmental effects, maternal deaths at high dose; monkey ePPND: no teratogenicity; no fertility effects in 6-month monkey study
“Reproductive and developmental toxicity studies were conducted in rats and monkeys; no teratogenic effects were observed at exposure margins of 12-fold and 81-fold, respectively. Alirocumab did not produce any effect on fertility parameters evaluated as part of the 6-month toxicity study in monkeys.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“Reproductive toxicity assessments were conducted in rats during the period of embryofetal development at up to 24-fold and in monkeys in an enhanced pre/postnatal development toxicity study at up to 81-fold the 150 mg Q2W human dose, based on plasma exposure.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waived on weight of evidence)
“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment, no preneoplastic or neoplastic lesions in rats or monkeys up to 6 months
“No preneoplastic or neoplastic lesions were observed that could be associated with alirocumab administration in rats or monkeys at up to 6 months duration. Based on a weight of evidence approach as outlined in the ICH-S6 guidance and discussed in detail in Section 8 of this review, alirocumab was not tested in an animal model for carcinogenesis.”
Carcinogenicity timing
Not required: waiver granted on weight of evidence (ICH S6)
“Weight of evidence supported the waiver of carcinogenicity studies with alirocumab; no formal carcinogenicity assessment was conducted, per ICH-S6.”
Safety marginopen answer page →
Safety margin at NOAEL
No significant adverse findings at up to 11-fold (rat) and 103-fold (monkey) human exposure at 150 mg Q2W
“No significant adverse findings were observed at the doses tested which achieved exposure multiples up to 11-fold in rats and 103-fold in monkeys compared to the maximum recommended human dose of 150 mg alirocumab administered subcutaneously once every two weeks.”
NOAEL / key findings
NOAEL at highest doses in 6-month studies (rat 50, monkey 75 mg/kg/week SC); no dose-limiting toxicity
“Alirocumab was subcutaneously administered for 6 months to rats at up to 50 mg/kg/week and to monkeys at up to 75 mg/kg/week; no evidence of dose-limiting test item-related toxicity was observed”
Efficacy evidenceopen answer page →
Efficacy evidence
APOE*Leiden.CETP mice on western diet, assessing lipid turnover and prevention of cardiovascular events
“One mouse study not only evaluated the effects of alirocumab on lipid turnover, but also the effects of alirocumab to prevent cardiovascular adverse events. Alirocumab, atorvastatin, or alirocumab/atorvastatin combination therapy was administered to APOE*Leiden.CETP mice fed a western diet.”
Why that model
Clinical antibody binds murine PCSK9, so it was active in hyperlipidaemic mouse models
“Administration of alirocumab to a hyperlipaemic ApoE-/- mouse model, which was also fed a modified diet, profoundly reduced serum LDL-C concentrations as a result of binding to murine PCSK-9.”
Reviewer's view of the efficacy data
Appropriate nonclinical program; expected cholesterol and LDL-C lowering in rats, hamsters and monkeys
“An appropriate nonclinical program was conducted by the sponsor to support approval of alirocumab. Alirocumab elicited expected pharmacological responses in rats, hamsters, and monkeys; alirocumab lowered total cholesterol and LDL-cholesterol in the species tested and decreased HDL-cholesterol in rats and hamsters.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity study for a chronic lipid-lowering antibody; waiver granted on weight of evidence
Why: No evidence of carcinogenic concern from sponsor data and published literature; ICH S6(R1) weight of evidence · Weight of evidence · Within the guideline
“Although the conduct of a carcinogenicity study in rats was likely feasible, the sponsor’s request for a waiver was granted based on lack of evidence for carcinogenic concern based on data provided by the sponsor and published literature.”
“Reviewer concluded that there is a lack of compelling evidence that would merit conducting rodent carcinogenicity studies with alirocumab based on the ICH-S6(R1) guidance.”
DARTAccepted
No dedicated fertility study; fertility endpoints assessed in the 26-week monkey toxicity study
Why: ICH S6(R1): primate is the most relevant species, fertility endpoints can be collected in repeat-dose toxicity study · Within the guideline
“A full assessment of endpoints related to fertility was conducted during a 26-week chronic toxicology study in sexually-mature monkeys (see the chronic monkey study in Section 6.2.2) per ICH-S6(R1).”
“For biologics, where the primate is the most relevant species, fertility endpoints can be collected in a repeat dose toxicity study, per ICH-S6.”
Safety pharmacologyVerdict not stated
No standalone safety pharmacology studies; endpoints integrated into rat and monkey toxicity studies
“Safety pharmacology endpoints were integrated in toxicology studies in both rats and Cynomolgus monkeys.”
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