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.”
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”
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 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 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.”
Similar precedents
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