Actemra
tocilizumab
Species
Monkey
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The cynomolgus monkey was chosen as the relevant responder species and a comprehensive toxicology program was conducted with single- and multiple-dose studies up to duration of 6 months to characterize the overall safety of tocilizumab.”
Why that species
Cross-reacts with monkey IL-6R in vitro and in vivo; no binding to rat, mouse or rabbit IL-6R
“The cynomolgus monkey was chosen as the pharmacologically relevant species because tocilizumab cross-reacts with monkey IL-6R under in vitro and in vivo conditions.”
Surrogate molecule
Yes: rodent analogue MR16-1 (anti-mouse IL-6R), used for supportive mouse toxicology studies
“Additionally supportive data from diverse studies conducted with the rodent analogue MR16-1 also were included in the assessment of the data.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Toxicity studies have shown tocilizumab to be well tolerated in cynomolgus monkeys, both as single intravenous (IV) doses up to 100 mg/kg and when given in multiple IV doses up to 50 mg/kg/day for 4 weeks or at IV doses up to 100 mg/kg/week for 6 months.”
Pivotal GLP studies
Cynomolgus monkey IV studies: 4-week daily up to 50 mg/kg/day and 6-month weekly up to 100 mg/kg/week
“Toxicity studies have shown tocilizumab to be well tolerated in cynomolgus monkeys, both as single intravenous (IV) doses up to 100 mg/kg and when given in multiple IV doses up to 50 mg/kg/day for 4 weeks or at IV doses up to 100 mg/kg/week for 6 months.”
Route in tox
IV
“Toxicity studies have shown tocilizumab to be well tolerated in cynomolgus monkeys, both as single intravenous (IV) doses up to 100 mg/kg and when given in multiple IV doses up to 50 mg/kg/day for 4 weeks or at IV doses up to 100 mg/kg/week for 6 months.”
Skipped studiesopen answer page →
Genotoxicity
No special hazard in conventional genotoxicity studies
“Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.”
Carcinogenicity
Not conducted; malignancy risk of IL-6 receptor blockade unknown
“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”
Reproductive & developmental
Monkey EFD: no teratogenicity; increased abortion/embryo-fetal death at 10 and 50 mg/kg (1.25x MRHD and higher)
“Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg.”
Safety pharmacology
Dedicated cardiovascular studies in cynomolgus monkeys; no effect on cardiac electrophysiology, cardiac tissue or pro-thrombotic activity up to 50 mg/kg IV
“Tocilizumab showed no effect on the cardiac electrophysiological performance, cardiac tissue integrity or systemic pro-thrombotic activities IV at doses up to 50 mg/kg.”
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 Actemra 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: No major clinical pathology or histopathology findings; exposure 8- to 10-fold above maximum human exposure (EMA assessment report, p. 16)
NOAEL / key findings
No major clinical pathology or histopathology findings; exposure 8- to 10-fold above maximum human exposure
“No major abnormal findings were observed in either the clinical pathology investigations or in the histopathological evaluation of tissues. The systemic steady state exposure to tocilizumab in these monkey studies was 8-to10-fold above the maximum human exposure”
Risksopen answer page →
Immune & cytokine safety
Immunogenic in monkeys with inverse dose relationship (ADA lower at high doses)
“The observed anti-tocilizumab response showed a clear inverse dose relationship, an effect which is frequently observed with molecules of this type.”
Biodistribution & persistence
Placental transfer: monkey fetal plasma 39% and 60% of maternal at 10 and 50 mg/kg/day
“In a segment II-embryo-foetal development study in cynomolgus monkeys foetal plasma concentrations of tocilizumab were 39% and 60% of the maternal plasma concentration after application of 10 and 50 mg/kg/day, resp.”
Modality-specific risk
Neutropenia from IL-6R blockade, without bone marrow changes in monkeys
“A signal toward reduction of neutrophils was observed in the 2-week toxicity study with a clear pronounced manifestation in the 4-week daily treatment cynomolgus study with no manifestation in the bone marrow.”