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.”
Species: general tox
Hamster (up to 3 months) and monkey (up to 6 months)
“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.”
Species: DART
Hamster (fertility, early embryonic) and cynomolgus monkey (enhanced pre/postnatal; fertility in 6-month study)
“The nonclinical reproductive and developmental safety profile of evolocumab was informed by three studies: (1) an enhanced pre-postnatal development study in cynomolgus monkeys, (2) a fertility and early embryonic development study in hamsters and (3) assessment of male and female fertility endpoints in the 6 month cynomolgus monkey study.”
Species: carcinogenicity
Hamster lifetime study (up to 2 years)
“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 for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”
Surrogate used in
No surrogate used; evolocumab tested in hamster and monkey, which express PCSK9 bound with high affinity
“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.”
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.”
Genotox: Ames
Not conducted (ICH S6)
“Under ICH-S6, genotoxic evaluation of evolocumab, a monoclonal antibody with no reasonable expectation of interacting with DNA, is not recommended.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Under ICH-S6, genotoxic evaluation of evolocumab, a monoclonal antibody with no reasonable expectation of interacting with DNA, is not recommended.”
Genotox: in vivo
Not conducted (ICH S6)
“Under ICH-S6, genotoxic evaluation of evolocumab, a monoclonal antibody with no reasonable expectation of interacting with DNA, is not recommended.”
Carcinogenicity model
Hamster lifetime (2-year) study, every other week dosing: no drug-related tumors at 38-, 15- and 6.6-fold human exposure
“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 for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”
Carcinogenicity timing
Hamster lifetime study completed before the marketing application; not carcinogenic
“Evolocumab was not carcinogenic in hamsters with lifetime dosing at up to 38, 15 and 6.6X the human exposures at the 140 mg Q2W, 420 mg QM and 420 mg Q2W doses.”
hERG / QT
Monkey telemetry (single IV 300 mg/kg): no adverse cardiovascular, respiratory, neurological or 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
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: 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.”
Anti-drug antibodies: animals
Hamster: not immunogenic; monkey ADA incidence ≤10%, some neutralising
“In hamster, evolocumab was not immunogenic. In Cynomolgus monkey the incidence of anti-evolocumab antibodies (antidrug antibodies, ADA) was not higher than 10%. In some animals these ADA were neutralising.”
Anti-drug antibodies: patients
0.3% (48/17,992) binding antibodies in adults; no neutralizing antibodies
“In a pool of placebo- and active-controlled clinical trials, 0.3% (48 out of 17,992) of adult patients treated with at least one dose of REPATHA tested positive for the development of binding antibodies. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.”
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 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
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: Monkey 26-week study: NOAEL 300 mg/kg/week, the highest dose tested (FDA pharmacology/toxicology review, p. 59)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey SC study (weekly) with 25-week recovery
“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.”
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.”
DART package
Species: DART
Hamster (fertility, early embryonic) and cynomolgus monkey (enhanced pre/postnatal; fertility in 6-month study)
“The nonclinical reproductive and developmental safety profile of evolocumab was informed by three studies: (1) an enhanced pre-postnatal development study in cynomolgus monkeys, (2) a fertility and early embryonic development study in hamsters and (3) assessment of male and female fertility endpoints in the 6 month cynomolgus monkey study.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“The Applicant performed an enhanced pre/postnatal developmental toxicity study in pregnant monkeys with administration of evolocumab at up to 50 mg/kg every other week by the subcutaneous route”
Carcinogenicity
Species: carcinogenicity
Hamster lifetime study (up to 2 years)
“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 for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”
Carcinogenicity model
Hamster lifetime (2-year) study, every other week dosing: no drug-related tumors at 38-, 15- and 6.6-fold human exposure
“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 for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”
Carcinogenicity timing
Hamster lifetime study completed before the marketing application; not carcinogenic
“Evolocumab was not carcinogenic in hamsters with lifetime dosing at up to 38, 15 and 6.6X the human exposures at the 140 mg Q2W, 420 mg QM and 420 mg Q2W doses.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 744x, 300x and 134x human exposure at 140 mg Q2W, 420 mg QM and 420 mg Q2W (hamster 112x, 48x, 20x)
“Based on plasma exposures measured in toxicity studies in hamsters, the safety margins for the 140 mg Q2W, 420 mg QM, and 420 mg Q2W doses are 112, 48 and 20X, respectively. In monkeys, the safety margins are 744, 300, and 134X the recommended human doses of 140 mg Q2W, 420 mg QM, and 420 mg Q2W, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cholesterol and LDL-C lowering in normal hamsters and monkeys
“Evolocumab elicited expected pharmacological responses in hamsters and monkeys; evolocumab lowered total cholesterol and LDL-cholesterol in the species tested and decreased HDL-cholesterol in hamsters.”
Why that model
Hamster and monkey express PCSK9 bound with high affinity, making them pharmacologically relevant species
“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.”
Reviewer's view of the efficacy data
EMA: comprehensive pharmacology and toxicology package supported the application
“A comprehensive pharmacological and toxicological data package was provided to support the application for evolocumab in treatment of adult patients with primary hypercholesterolemia or mixed dyslipidaemia and in adults and adolescents with homozygous familial hypercholesterolemia.”
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
Combination toxicity study used a rosuvastatin dose without pharmacological activity in monkeys
Why: Study adequately characterised the potential for combinatorial toxicity despite caveats
“The low dose (5 mg/kg) may explain the lack of pharmacological activity of rosuvastatin but does not justify the dose selection for the study; according to the publically available data, the therapeutic range seems to be higher than the 5 mg/kg used in the toxicological study.”
“Despite the caveats noted above, the study is acceptable as having adequately characterized the potential for combinatorial toxicity when a statin is used in”
OtherAccepted with a conditionBeyond the letter
TDAR immunotoxicity re-analysis not accepted as justified; concern about impaired T-cell-dependent antibody response remained
“The re-analysis of available TDAR data was not considered however appropriately justified, and since the full data set had to be taken into consideration, the concern of potential risk of impairment of T cell dependent antibody response at least after long term treatment (3 months) remained.”
“Whether or not the reduced TDAR upon evolocumab treatment in monkey would be a risk in humans, was uncertain and is reflected in section 5.3 of the SmPC.”
DARTVerdict not stated
Effects on infant humoral immunity not evaluated in developmental studies despite a class signal with alirocumab
“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.”
Similar precedents
PraluentAntibodies · alirocumab · PCSK9Monkey + rodent · 26 wkLeqvioOligos · inclisiran · PCSK9 (siRNA)Monkey + rodent · 40 wkEvkeezaAntibodies · evinacumab · ANGPTL3Monkey + rodent · 26 wkAdbryAntibodies · tralokinumab · IL-13Monkey only · 26 wkAlhemoAntibodies · concizumab · TFPIMonkey only · 52 wkAvastinAntibodies · bevacizumab · VEGF-AMonkey only · 26 wk