Kevzara
sarilumab
Species
Monkey
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 only
“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing since only monkeys were identified as a relevant species for sarilumab in a series of pharmacology studies.”
Why that species
Binds human and cynomolgus IL-6Ra (KD 54 and 123 pM); no binding to murine IL-6Ra
“Sarilumab binds human and Cynomolgus monkey IL-6Rα with an equilibrium dissociation constant (Kd) of 54 pM and 123 pM, respectively, but no binding of sarilumab to the murine IL-6Rα was observed.”
Surrogate molecule
Yes: murine anti-mouse IL-6Ra surrogate REGN844, used for mouse fertility and juvenile toxicity studies
“Fertility and juvenile toxicity studies were also conducted in mice with an analogous monoclonal antibody (REGN844).”
Species: general tox
Cynomolgus monkey only
“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing since only monkeys were identified as a relevant species for sarilumab in a series of pharmacology studies.”
Species: DART
Cynomolgus monkey (ePPND) and mouse (fertility, with surrogate REGN844)
“The reproductive and developmental toxicity of sarilumab was evaluated in an enhanced pre- and postnatal development (ePPND) study in cynomolgus monkeys. Further, a murine surrogate monoclonal antibody to sarilumab that binds mouse IL-6Rα (i.e., REGN844) was developed and used for a fertility study in mice.”
Species: carcinogenicity
Not conducted: rodent study not feasible due to species specificity
“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”
Surrogate used in
Yes: mouse surrogate REGN844 for fertility and juvenile toxicity studies
“Fertility and juvenile toxicity studies were also conducted in mice with an analogous monoclonal antibody (REGN844).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Four monkeys/sex/group were sacrificed after the 26-week dosing period and the remaining 2 monkeys/sex/group were sacrificed after a 12-week recovery period.”
Pivotal GLP studies
GLP cynomolgus repeat-dose studies: IV for up to 6 months and SC for 3 months
“The toxicity profile of sarilumab was evaluated in a number of GLP compliant repeat-dose toxicology studies in Cynomolgus monkeys by the intravenous (IV) route of administration for up to 6 months in duration and by the SC route for 3 months duration.”
Route in tox
Intravenous and subcutaneous
“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not applicable to a monoclonal antibody)
“Genetic toxicity studies were not applicable for this therapeutic biologic monoclonal antibody.”
Carcinogenicity
Not conducted: rodent study not feasible due to species specificity; ECAC concurred
“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”
Reproductive & developmental
Mouse fertility unaffected (REGN844); monkey ePPND: no neonatal effects, NOAEL 50 mg/kg/week
“There were no observed effects on fertility in mice. In an expanded prenatal and postnatal development study in monkeys, no effects on evaluated parameters in neonates were observed. The NOAEL was the high dose of 50 mg/kg/week.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or CNS effects
“No sarilumab-related effects were observed on cardiovascular, respiratory or CNS functions.”
Genotox: Ames
Not conducted (monoclonal antibody)
“Genetic toxicity studies were not applicable for this therapeutic biologic monoclonal antibody.”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody)
“Genetic toxicity studies were not applicable for this therapeutic biologic monoclonal antibody.”
Genotox: in vivo
Not conducted (monoclonal antibody)
“Genetic toxicity studies were not applicable for this therapeutic biologic monoclonal antibody.”
Carcinogenicity model
Not conducted: rodent study not feasible (species specificity); weight-of-evidence risk assessment instead
“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”
Carcinogenicity timing
Not required; ECAC concurred no study feasible
“The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible. No nonclinical studies were required to evaluate the potential carcinogenicity of sarilumab.”
hERG / QT
No hERG assay; no cardiovascular, respiratory or CNS effects in monkey repeat-dose studies
“No sarilumab-related effects were observed on cardiovascular, respiratory or CNS functions.”
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 Kevzara 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 50 mg/kg/week (high dose) in pivotal monkey study; no target organs of toxicity; >80-fold exposure margin (FDA pharmacology/toxicology review, p. 47)
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in pivotal monkey study; no target organs of toxicity; >80-fold exposure margin
“The NOAEL was identified at the high dose of 50 mg/kg/week based upon no findings of dose-limiting toxicity or target organs of toxicity. Exposure at the NOAEL provided a safety margin >80 times the exposures at proposed clinical doses.”
Risksopen answer page →
Immune & cytokine safety
Small decreases in primary and secondary IgG TDAR responses to KLH at >=5 mg/kg/week, attributed to immunosuppression
“From the TDAR assessment, there were small decreases in both the primary and secondary IgG responses to KLH challenge in males and females that received doses ≥5 mg/kg/week; this change was attributed to the immunosuppressive properties of sarilumab.”
Biodistribution & persistence
TCR: similar human and monkey staining, cytoplasmic only in human tissues (no membrane sites)
“The positive tissue staining for biotinylated sarilumab between human and monkey tissues appeared similar with some exceptions. In human tissues, positive staining for biotinylated sarilumab was detected in the cytoplasm and/or cytoplasmic granules of various sites but not at any membrane sites.”
Modality-specific risk
Immune suppression-mediated tumor initiation or promotion from IL-6R blockade, managed by labeling
“that it was reasonable to manage risk for immune suppression mediated tumor initiation and/or tumor promotion by appropriate labeling.”
Anti-drug antibodies: animals
ADA in monkeys associated with lower sarilumab exposure but no adverse effects
“The presence of ADAs was associated with lower exposure to sarilumab, but was not associated with any adverse effects.”
Anti-drug antibodies: patients
ADA 4.0% (200 mg) and 5.7% (150 mg) with DMARD in RA; NAb 1.0% and 1.6%
“In the RA pre-rescue population, 4.0% of patients treated with KEVZARA 200 mg + DMARD, 5.7% of patients treated with KEVZARA 150 mg + DMARD and 1.9% of patients treated with placebo + DMARD, exhibited an anti-drug antibody (ADA) response. Neutralizing antibodies (NAb) were detected in 1.0% of patients on KEVZARA 200 mg + DMARD, 1.6% of patients on KEVZARA 150 mg + DMARD, and 0.2% of patients on placebo + DMARD.”
Label warnings
Boxed warning: Risk of serious infections
- Serious Infections
- Laboratory Abnormalities
- Gastrointestinal Perforation
- Immunosuppression
- Hypersensitivity Reactions
- Active Hepatic Disease and Hepatic Impairment
- Live Vaccines
InfectionsGastrointestinalHypersensitivity & infusion reactionsHepatotoxicity
US prescribing information, Boxed Warning and 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 Kevzara 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 50 mg/kg/week (high dose) in pivotal monkey study; no target organs of toxicity; >80-fold exposure margin (FDA pharmacology/toxicology review, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV, weekly) with 12-week recovery
“Four monkeys/sex/group were sacrificed after the 26-week dosing period and the remaining 2 monkeys/sex/group were sacrificed after a 12-week recovery period.”
Pivotal GLP studies
GLP cynomolgus repeat-dose studies: IV for up to 6 months and SC for 3 months
“The toxicity profile of sarilumab was evaluated in a number of GLP compliant repeat-dose toxicology studies in Cynomolgus monkeys by the intravenous (IV) route of administration for up to 6 months in duration and by the SC route for 3 months duration.”
DART package
Species: DART
Cynomolgus monkey (ePPND) and mouse (fertility, with surrogate REGN844)
“The reproductive and developmental toxicity of sarilumab was evaluated in an enhanced pre- and postnatal development (ePPND) study in cynomolgus monkeys. Further, a murine surrogate monoclonal antibody to sarilumab that binds mouse IL-6Rα (i.e., REGN844) was developed and used for a fertility study in mice.”
Reproductive & developmental
Mouse fertility unaffected (REGN844); monkey ePPND: no neonatal effects, NOAEL 50 mg/kg/week
“There were no observed effects on fertility in mice. In an expanded prenatal and postnatal development study in monkeys, no effects on evaluated parameters in neonates were observed. The NOAEL was the high dose of 50 mg/kg/week.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed and submitted with the marketing application
“The reproductive and developmental toxicity of sarilumab was evaluated in an enhanced pre- and postnatal development (ePPND) study in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted: rodent study not feasible due to species specificity
“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”
Carcinogenicity model
Not conducted: rodent study not feasible (species specificity); weight-of-evidence risk assessment instead
“Based on species specificity, a rodent carcinogenicity study with sarilumab was not considered feasible. The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible.”
Carcinogenicity timing
Not required; ECAC concurred no study feasible
“The Executive Carcinogenicity Assessment Committee (ECAC) concurred that a carcinogenicity study was not feasible. No nonclinical studies were required to evaluate the potential carcinogenicity of sarilumab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 6-month NOAEL 50 mg/kg/week >80x human systemic exposure at recommended doses
“The NOAEL of 50 mg/kg/week from the 6-month study provided a safety margin of > 80-fold compared to the recommended clinical doses based on systemic exposure comparisons.”
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in pivotal monkey study; no target organs of toxicity; >80-fold exposure margin
“The NOAEL was identified at the high dose of 50 mg/kg/week based upon no findings of dose-limiting toxicity or target organs of toxicity. Exposure at the NOAEL provided a safety margin >80 times the exposures at proposed clinical doses.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse collagen-induced arthritis with surrogate REGN844 (prophylactic); prevented joint inflammation and bone erosion
“Pertinent to the proposed indication of rheumatoid arthritis, the effect of blocking IL-6Rα was evaluated in a murine model of collagen-induced arthritis. In a prophylactic setting, REGN844 prevented development of joint inflammation and bone erosion.”
Why that model
Sarilumab does not bind murine IL-6Rα; humanized mice or a mouse surrogate were required
“Sarilumab binds human and Cynomolgus monkey IL-6Rα with an equilibrium dissociation constant (Kd) of 54 pM and 123 pM, respectively, but no binding of sarilumab to the murine IL-6Rα was observed.”
Reviewer's view of the efficacy data
EMA: surrogate CIA data provide proof-of-concept for IL-6Rα blockade in arthritis
“Sarilumab murine surrogate was able to mitigate disease signs and severity (swelling of the joints, bone erosion) of induced autoimmune rheumatoid arthritis in CIA model. These data provide a proof-of-concept for the blockade of IL-6Rα in arthritis.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic rheumatoid arthritis use; carcinogenicity risk assessment accepted by ECAC, with risk managed in labeling
Why: Carcinogenicity risk assessment accepted; immune-suppression tumour risk managed through labeling · Weight of evidence
“The sponsor submitted a carcinogenicity risk assessment for sarilumab and the Executive Carcinogenicity Assessment Committee agreed with the Division that no additional studies were required to address the carcinogenic potential of sarilumab and that it was reasonable to manage risk for immune suppression mediated tumor initiation and/or tumor promotion by appropriate labeling.”
DARTVerdict not stated
Fertility and juvenile toxicity studied only in mice with an analogous anti-mouse IL-6R antibody (REGN844)
Why: Only monkeys are a relevant species for sarilumab · No relevant species
“Pivotal nonclinical studies of sarilumab were conducted in Cynomolgus monkeys by intravenous and SC dosing since only monkeys were identified as a relevant species for sarilumab in a series of pharmacology studies. Fertility and juvenile toxicity studies were also conducted in mice with an analogous monoclonal antibody (REGN844).”
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