Enspryng
satralizumab
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
“The pivotal studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Why that species
Cross-reacts with cynomolgus IL-6R but not mouse or rat IL-6R
“Satralizumab showed cross-reactivity in cynomolgus monkey but not in mice or rats. Based on these data, monkey was selected as the relevant species for nonclinical testing of satralizumab.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys (mouse homolog judged not feasible due to immunogenicity)
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Species: general tox
Cynomolgus monkey only
“The pivotal studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Species: DART
Cynomolgus monkey (ePPND, 0, 2 and 50 mg/kg/week SC)
“In the ePPND study, administration of satralizumab (0, 2, and 50 mg/kg/week SC) to pregnant females resulted in a dose-dependent reduction in the antibody responses to antigenic challenge in infants.”
Species: carcinogenicity
Not conducted (no rat or mouse IL-6R binding; mouse homolog not feasible)
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Surrogate used in
No surrogate used; mouse homolog antibody judged not feasible because of immunogenicity
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In general toxicity studies in monkey, weekly subcutaneous doses of up to 50 mg/kg for 4 or 26 weeks resulted in no notable toxicity or effects on male (sperm analysis) and female (menstrual cycle) reproductive parameters and organs.”
Pivotal GLP studies
Cynomolgus monkey 4- and 26-week studies, weekly SC up to 50 mg/kg; monkey ePPND
“In general toxicity studies in monkey, weekly subcutaneous doses of up to 50 mg/kg for 4 or 26 weeks resulted in no notable toxicity or effects on male (sperm analysis) and female (menstrual cycle) reproductive parameters and organs.”
Route in tox
Subcutaneous
“In the general toxicity studies, no adverse effects were observed in monkeys administered satralizumab (0, 2, 10, or 50 mg/kg/week SC) for 4 or 26 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (antibodies unable to interact with genetic material)
“No genotoxicity studies of satralizumab were conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity
Not conducted (no rodent IL-6R binding; mouse homolog not feasible); human malignancy risk unknown
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Reproductive & developmental
Monkey ePPND (0, 2, 50 mg/kg/week SC): dose-dependent reduction in infant antibody responses to antigen challenge
“In the ePPND study, administration of satralizumab (0, 2, and 50 mg/kg/week SC) to pregnant females resulted in a dose-dependent reduction in the antibody responses to antigenic challenge in infants.”
Safety pharmacology
Incorporated into pivotal monkey toxicology studies
“No stand-alone safety pharmacology studies of satralizumab were submitted. Safety pharmacology assessments were incorporated into the pivotal toxicology studies of satralizumab in monkey.”
Genotox: Ames
Not conducted (antibodies unable to interact with genetic material)
“No genotoxicity studies of satralizumab were conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vitro mammalian
Not conducted (antibodies unable to interact with genetic material)
“No genotoxicity studies of satralizumab were conducted because antibodies are generally unable to interact with genetic material.”
Genotox: in vivo
Not conducted (antibodies unable to interact with genetic material)
“No genotoxicity studies of satralizumab were conducted because antibodies are generally unable to interact with genetic material.”
Carcinogenicity model
Not conducted (no rodent IL-6R binding; mouse homolog not feasible due to immunogenicity)
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Carcinogenicity timing
Not required (Division agreement, June 2016)
“The Division informed the sponsor that carcinogenicity studies of satralizumab would not be required to support a BLA (see email of June 14, 2016).”
hERG / QT
No hERG assay; no ECG, blood pressure, respiratory or CNS effects in monkeys at 2-50 mg/kg weekly SC for 4 or 26 weeks
“No significant effects on cardiovascular (electrocardiogram (ECG), blood pressure), respiratory, or central nervous system functions were shown following subcutaneous administration of 2, 10 and 50 mg/kg satralizumab once weekly for 4 or 26 weeks with exposure levels providing acceptable margins to the clinical exposure.”
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 Enspryng 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 26-week SC monkey study; no notable toxicity (FDA pharmacology/toxicology review, p. 32)
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in 26-week SC monkey study; no notable toxicity
“The NOAEL was the high dose of 50 mg/kg/week.”
Risksopen answer page →
Immune & cytokine safety
Low cytokine release syndrome risk in human whole-blood cytokine assay
“Based on a human in vitro blood cytokine assay, the potential of satralizumab to induce a cytokine release syndrome (CRS) is considered to be low in terms of incidence and increase in cytokines.”
Biodistribution & persistence
TCR: similar human and monkey staining consistent with IL-6R expression (adrenal, liver, macrophages, lymphocytes)
“The staining pattern produced was consistent with what is known regarding IL-6R expression in e.g. adrenal cells, liver, macrophages, and lymphocytes, and the staining pattern was similar in human and Cynomolgus monkey tissue.”
Modality-specific risk
Immunosuppression from IL-6R blockade: impaired antibody responses in exposed infants (infection, vaccine response risk)
“However, infants of women treated with satralizumab during pregnancy may be at increased risk of adverse effects such as infection or impaired response to vaccinations.”
Anti-drug antibodies: animals
ADA in 12-22% of monkeys, some neutralizing, often with reduced exposure (excluded from TK); study validity retained
“ADAs development was commonly seen in the studies in monkey (overall incidence of 12-22%), and some animals showed neutralization activity. These animals often showed reduced exposure to satralizumab and were excluded in the TK calculations.”
Anti-drug antibodies: patients
73% (Study 1) and 38% (Study 2) in double-blind period; neutralizing ability unknown
“In Study 1 and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown.”
Label warnings
- Infections
- Elevated Liver Enzymes
- Decreased Neutrophil Counts
- Hypersensitivity Reactions
InfectionsHepatotoxicityHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Japan: early study in healthy volunteers (SA-001JG); another in RA patients
“In addition, two Phase I studies have been conducted in Japan, one in healthy volunteers (SA-001JG) and one in RA patients (SA-105JG).”
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 Enspryng 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 26-week SC monkey study; no notable toxicity (FDA pharmacology/toxicology review, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (SC) GLP study with 13-week recovery
“one GLP 26-week study (with 13-week recovery) using once-weekly SC administration.”
Pivotal GLP studies
Cynomolgus monkey 4- and 26-week studies, weekly SC up to 50 mg/kg; monkey ePPND
“In general toxicity studies in monkey, weekly subcutaneous doses of up to 50 mg/kg for 4 or 26 weeks resulted in no notable toxicity or effects on male (sperm analysis) and female (menstrual cycle) reproductive parameters and organs.”
DART package
Species: DART
Cynomolgus monkey (ePPND, 0, 2 and 50 mg/kg/week SC)
“In the ePPND study, administration of satralizumab (0, 2, and 50 mg/kg/week SC) to pregnant females resulted in a dose-dependent reduction in the antibody responses to antigenic challenge in infants.”
Reproductive & developmental
Monkey ePPND (0, 2, 50 mg/kg/week SC): dose-dependent reduction in infant antibody responses to antigen challenge
“In the ePPND study, administration of satralizumab (0, 2, and 50 mg/kg/week SC) to pregnant females resulted in a dose-dependent reduction in the antibody responses to antigenic challenge in infants.”
PPND / ePPND: when
ePPND in cynomolgus monkey completed and submitted in the marketing application
“The pivotal nonclinical studies submitted in the BLA consist of pharmacology, PK, and toxicity (including 4- and 26-week) studies, and an enhanced pre- and postnatal development (ePPND) study.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no rat or mouse IL-6R binding; mouse homolog not feasible)
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Carcinogenicity model
Not conducted (no rodent IL-6R binding; mouse homolog not feasible due to immunogenicity)
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
Carcinogenicity timing
Not required (Division agreement, June 2016)
“The Division informed the sponsor that carcinogenicity studies of satralizumab would not be required to support a BLA (see email of June 14, 2016).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL (26-week and ePPND maternal) ~26x human steady-state AUC
“As illustrated in Table 2 below, predicted satralizumab plasma exposures (AUC) in humans at steady-state during treatment with the proposed clinical dose were 26-fold lower than those observed at the maternal NOAEL in the ePPND study and at the HD (NOAEL) in the pivotal 26-week study.”
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in 26-week SC monkey study; no notable toxicity
“The NOAEL was the high dose of 50 mg/kg/week.”
Efficacy evidenceopen answer page →
Efficacy evidence
Normal cynomolgus monkeys: inhibition of IL-6-stimulated CRP production and soluble IL-6R binding (vs tocilizumab)
“The pharmacology of satralizumab and tocilizumab was studied in terms of inhibitory effects on IL-6-stimulated C-reactive protein (CRP) production (i.e. on classical signaling), free and total (both free IL-6R and receptor bound to satralizumab) soluble IL-6R concentration (i.e. on trans-signaling).”
Why that model
No NMOSD model established in monkeys, the only cross-reactive species
“As satralizumab showed cross-reactivity in cynomolgus monkey but not in mice or rats, in vivo pharmacology of satralizumab was studied in cynomolgus monkeys. The efficacy of satralizumab in NMOSD models in vivo have not been investigated since no NMOSD model has been established in monkeys.”
Reviewer's view of the efficacy data
EMA: CRP and soluble IL-6R are non-specific biomarkers and no disease model was studied; further mechanistic clarification required
“However, given that CRP and free soluble IL-6R are both general inflammatory biomarkers not specific for NMOSD and that satralizumab has not been studied in any disease model in vivo, additional clarification regarding the mechanism of action of satralizumab and the role of classical signalling and trans-signalling in NMO was required by the Applicant.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic NMOSD indication; no rodent IL-6R binding and mouse homolog not feasible
Why: No binding to rodent IL-6R; mouse homolog antibody not feasible because of immunogenicity · No relevant species · Other reason
“Carcinogenicity studies of satralizumab were not conducted because satralizumab does not bind to rat or mouse IL-6R, and the use of a mouse homolog antibody was determined not to be feasible because of immunogenicity.”
“The Division and the Executive Carcinogenicity Assessment Committee agreed (June 14, 2016) with the sponsor’s justification for not conducting carcinogenicity studies of satralizumab.”
Safety marginVerdict not stated
No safety margin established for reduced T-cell-dependent antibody responses in infants in the monkey ePPND study
“In summary, no safety margin was established for the reductions in TDAR observed in infants in the ePPND study.”
Juvenile toxAcceptedBeyond the letter
No stand-alone juvenile toxicity study; monkey ePPND study used instead
Why: ePPND study conducted in compliance with the agreed paediatric investigation plan · Other reason
“However, the ePPND study performed was conducted in compliance with the agreed PIP, why no further studies were considered needed.”
OtherCriticised but acceptedBeyond the letter
No tissue distribution study and no justification provided for its omission
Why: Limited tissue distribution from volume of distribution; no target organs in monkey toxicity studies · Pharmacology or kinetics · Weight of evidence
“A justification why no standard tissue distribution study, which might have revealed valuable information (e.g. potential for passage over the blood-brain-barrier to CNS), have been performed was not provided.”
“Furthermore, the available data and information, i.e. a volume of distribution that indicates limited tissue distribution together with that no toxicological target organs or tissues were identified in the toxicological studies in cynomolgus monkey, did not raise any concerns.”
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