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.”
Species: general tox
Cynomolgus monkey only (single and repeat dose up to 6 months)
“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.”
Species: DART
Cynomolgus monkey (EFD); mouse with murine analogue (fertility, pre/postnatal)
“An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50.”
Species: carcinogenicity
Not conducted
“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”
Surrogate used in
Yes: murine analogue of tocilizumab in mice for pre/postnatal development (and fertility)
“Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning).”
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.”
Genotox: Ames
No special hazard in conventional genotoxicity studies (individual assays not named)
“Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.”
Genotox: in vitro mammalian
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.
Genotox: in vivo
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.
Carcinogenicity model
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.”
Carcinogenicity timing
Not conducted: no long-term animal carcinogenicity studies performed
“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”
hERG / QT
Monkey in vivo cardiovascular studies: no effect on cardiac electrophysiology 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
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: 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.”
Anti-drug antibodies: animals
Immunogenic in monkeys; neutralizing ADA greatly diminished or absent at high dose; did not compromise study validity
“Neutralizing antibodies were either greatly diminished or not detected in animals treated with high dose tocilizumab. Thus, the observed immunogenicity of tocilizumab in cynomolgus monkey studies did not compromise the results of these studies and their relevance for risk extrapolation to humans.”
Anti-drug antibodies: patients
2% anti-tocilizumab antibody positive (5 with hypersensitivity leading to withdrawal); 1% neutralizing
“Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.”
Label warnings
Boxed warning: Risk of serious infections
- Serious Infections
- Gastrointestinal Perforations
- Hepatotoxicity
- Changes in Laboratory Parameters
- Immunosuppression
- Hypersensitivity Reactions, Including Anaphylaxis
- Demyelinating Disorders
- Active Hepatic Disease and Hepatic Impairment
- Vaccinations
InfectionsGastrointestinalHepatotoxicityHypersensitivity & infusion reactionsNeurotoxicity
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 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
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: No major clinical pathology or histopathology findings; exposure 8- to 10-fold above maximum human exposure (EMA assessment report, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) cynomolgus monkey IV study, up to 100 mg/kg/week; recovery phase not stated
“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.”
DART package
Species: DART
Cynomolgus monkey (EFD); mouse with murine analogue (fertility, pre/postnatal)
“An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50.”
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.”
PPND / ePPND: when
Mouse PPND with murine analogue reported in label; timing relative to marketing application not stated
“Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not conducted: no long-term animal carcinogenicity studies performed
“No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey steady-state trough exposure 8- to 10-fold above maximum human exposure
“The systemic steady state exposure to tocilizumab in these monkey studies was 8-to10-fold above the maximum human exposure comparing trough levels in the animals with the maximum level measured in clinical trials.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Cynomolgus monkey collagen-induced arthritis model
“In a cynomolgus monkey model of collagen-induced arthritis (CIA), tocilizumab was shown to prevent both the local joint and the systemic inflammatory disease manifestations.”
Why that model
Tocilizumab cross-reacts with monkey IL-6R; it does not bind 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.”
Reviewer's view of the efficacy data
EMA: pharmacology programme showed specific binding to soluble and membrane IL-6R and blockade of IL-6 activity
“The preclinical pharmacology programme showed that tocilizumab specifically binds to the IL-6 binding site of both sIL-6R and mIL-6R with similar affinity. Therefore, tocilizumab is able to block IL-6 from binding to both receptors and thereby blocks the activity of IL-6.”
Flexibilityopen answer page →
Flexibility accepted
GLPVerdict not stated
Safety pharmacology studies, including monkey cardiovascular studies, not conducted under formal GLP
“Safety pharmacology studies, including cardiovascular safety studies in the cynomolgus monkey, conducted during preclinical development were not done under formal GLP requirements.”
DARTAcceptedBeyond the letter
No dedicated fertility study; fertility risk inferred from chronic monkey toxicity and IL-6 deficient mice
Why: No reproductive organ effects in chronic monkey study; reproductive performance unaffected in IL-6 deficient mice · Weight of evidence
“Nonclinical data do not suggest an effect on fertility under treatment with tocilizumab as effects on endocrine active organs or on organs of the reproductive system were not seen in a chronic primate toxicity study.”
“There is also no preclinical evidence, that IL-6 signalling is involved in processes of reproduction, and, accordingly, the reproductive performance is not affected in IL-6 deficient mice.”
DARTVerdict not stated
Pre- and postnatal development assessed only with a murine analogue in mice, not tocilizumab
“Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning).”
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