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).”
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.”
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 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 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.”