Repatha
evolocumab
Species
Monkey
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
Hamster and cynomolgus monkey
“The Applicant identified the hamster and monkey as pharmacologically relevant species for toxicology testing with evolocumab; both species express PCSK9, to which evolocumab binds with high affinity.”
Why that species
High-affinity binding to human, cynomolgus monkey and hamster PCSK9 (KD 16, 8 and 14 pM)
“Evolocumab binds to human, cynomolgus monkey and hamster PCSK9 with high affinity (KD = 16, 8 and 14 pM, respectively; see Table 2).”
Surrogate molecule
No surrogate; the clinical antibody was tested in hamster and cynomolgus monkey
“Evolocumab is pharmacological active in human, Cynomolgous monkey and hamster. The latter two were used in toxicology studies, where also the pharmacodynamics parameters were measured.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection.”
Pivotal GLP studies
Hamster up to 3 months and cynomolgus monkey up to 6 months, once-weekly SC
“The primary nonclinical toxicity studies of evolocumab were conducted in hamsters for up to 3 months and monkeys for up to 6 months duration with once weekly subcutaneous dosing.”
Route in tox
SC (once weekly)
“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Evolocumab is not expected to interact directly with DNA and mutagenicity studies were not conducted, per ICH-S6.”
Carcinogenicity
Lifetime (2-year) hamster study, Q2W dosing: no drug-related tumors at 38-, 15- and 6.6-fold safety margins
“Evolocumab did not cause any drug-related tumors when administered to hamsters for up to 2 years in a lifetime carcinogenicity assay at doses administered once every other week that provide a 38-, 15- and 6.6-fold safety margin”
Reproductive & developmental
Expanded monkey developmental study with infants followed 6 months: no significant drug-related effects
“In an expanded developmental study in monkeys in which offspring were followed into infancy for 6 months, no significant drug-related effects were observed.”
Safety pharmacology
Single IV 300 mg/kg telemetry study in monkeys: no adverse cardiovascular, respiratory, neurological or body temperature effects
“When administered as a single intravenous dose of 300 mg/kg to conscious telemetry-instrumented cynomolgus monkeys, evolocumab (AMG 145) was well-tolerated and had no adverse effects on cardiovascular function, respiration rate, neurological behavior, or body temperature.”
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 Repatha 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: Monkey 26-week study: NOAEL 300 mg/kg/week, the highest dose tested (FDA pharmacology/toxicology review, p. 59)
NOAEL / key findings
Monkey 26-week study: NOAEL 300 mg/kg/week, the highest dose tested
“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection. Two monkeys/sex/group were allowed a 25-week treatment-free recovery period. The NOAEL is considered to be 300 mg/kg/week, the highest dose tested.”
Risksopen answer page →
Immune & cytokine safety
Apparent TDAR suppression in monkeys was no longer significant after restricting analysis to KLH-naive animals
“Since the interpretation of the TDAR relies on comparisons between groups of KLH-naïve animals, these animals were excluded from the TDAR analysis; the results were no longer statistically significant.”
Biodistribution & persistence
Crosses placenta: infant monkey serum levels at birth comparable to maternal levels
“Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier.”
Modality-specific risk
Possible humoral immune suppression in infants exposed in utero (seen with alirocumab); not evaluated for evolocumab
“Of note, humoral immune suppression was observed in infant monkeys exposed in utero to another drug in this class (alirocumab); effects on humoral immunity were not evaluated in the developmental studies for the evolocumab program.”