Sylvant
siltuximab
Species
MonkeyMouse
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 (fertility in mice with surrogate antibody)
“General toxicology studies, the embryo-fetal developmental study, and the enhanced pre- and post-natal developmental study (ePPND) were conducted in the cynomolgus monkey, a pharmacologically relevant species.”
Why that species
Neutralizes human and non-human primate IL-6; does not inhibit mouse, rat, dog, pig or guinea pig IL-6
“Siltuximab binds to and neutralizes human and non-human primate IL-6 but does not inhibit mouse, rat, dog, pig or guinea pig IL-6. Therefore, the cynomolgus monkey was selected as a pharmacologically relevant species for the toxicology and pharmacokinetics evaluation of siltuximab.”
Surrogate molecule
Yes: rat anti-mouse IL-6 mAb (CNTO 345) for mouse fertility studies; humanized siltuximab variant (CNTO 136) for monkey ePPND
“A fertility study was conducted with a rat anti-mouse IL6 mAb (CNTO 345) in mice and an enhanced pre- and post-natal development (ePPND) study was conducted with a humanized version of siltuximab (CNTO 136) in cynomolgus monkeys.”
Species: general tox
Cynomolgus monkey only (rodents and dogs not pharmacologically responsive)
“Toxicology studies were conducted using cynomolgus monkeys because other species available for toxicity testing (rodents and dogs) are not pharmacologically responsive to siltuximab.”
Species: DART
Cynomolgus monkey (EFD) and mouse (male and female fertility, with surrogate CNTO 345)
“The potential developmental and reproductive toxicity of siltuximab was investigated in an embryofetal development study in cynomolgus monkeys (T-205-036). Supportive fertility studies in male (Study T-2010-033) and female (Study T-2010-032) mice were conducted using the rat IgG1 isotype anti-mouse IL-6 mAb CNTO 345.”
Species: carcinogenicity
Not conducted (not needed)
“Genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Surrogate used in
Yes: rat anti-mouse IL-6 mAb CNTO 345 for mouse fertility; humanized siltuximab CNTO 136 for monkey ePPND
“A fertility study was conducted with a rat anti-mouse IL6 mAb (CNTO 345) in mice and an enhanced pre- and post-natal development (ePPND) study was conducted with a humanized version of siltuximab (CNTO 136) in cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Repeat dose toxicology studies of 3-months or 6-months duration with extended recovery periods were conducted using weekly IV infusion administration of 9.6 or 46 mg/kg/dose siltuximab alone or in combination with IL-2 administration.”
Pivotal GLP studies
Cynomolgus monkey 3- and 6-month studies, weekly IV infusion 9.6 or 46 mg/kg, plus 3-month combination study with IL-2
“Repeat dose toxicology studies of 3-months or 6-months duration with extended recovery periods were conducted using weekly IV infusion administration of 9.6 or 46 mg/kg/dose siltuximab alone or in combination with IL-2 administration.”
Route in tox
Intravenous (2-hour infusion, once weekly)
“The repeat-dose toxicity of siltuximab was evaluated following once a week (q1w) IV 2-hour infusion of 9.2 and 46 mg/kg doses of siltuximab in 3- and 6-month studies (Study T-2002-007 and T-2003-010).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted or needed per ICH S6 guidance.”
Carcinogenicity
Not conducted; weight-of-evidence suggests low risk, but reduced immune surveillance means increased tumor susceptibility cannot be ruled out
“Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.”
Reproductive & developmental
Monkey EFD and ePPND (humanized analog): placental transfer, reduced globulin in dams and offspring; mouse surrogate fertility studies negative
“Siltuximab crossed the placenta and resulted in reduced globulin levels in pregnant animals and in the offspring; this may be secondary to a decreased production of immunoglobulin as expected from the pharmacology of this product.”
Safety pharmacology
Incorporated into 3- and 6-month monkey studies (ECG, BP, respiration, CNS observations); no siltuximab-related adverse effects
“No siltuximab treatment–related adverse effects on safety pharmacology parameters were observed in the 3 and 6 months toxicology studies.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted or needed per ICH S6 guidance.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted or needed per ICH S6 guidance.”
Genotox: in vivo
Not conducted (ICH S6)
“Genetic toxicology studies were not conducted or needed per ICH S6 guidance.”
Carcinogenicity model
Not conducted; weight of evidence suggests low potential, but increased susceptibility to specific tumors not ruled out
“Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.”
Carcinogenicity timing
Not required for this application
“Genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
hERG / QT
No hERG assay; monkey ECGs in 3- and 6-month studies normal apart from isolated premature complexes
“All ECGs were normal in siltuximab-dosed animals in the 3 and 6-month toxicology studies, with the exception of isolated ventricular premature complexes (VPCs) seen in 2 monkeys administered 46 mg/kg, and arterial premature complexes (APCs) seen at in 1 male administered 9.2 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 Sylvant 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 significant toxicities in 3- or 6-month monkey studies; pharmacology-related lower globulin, reduced TDAR, smaller splenic germinal centers, skin erythema (FDA pharmacology/toxicology review, p. 16)
NOAEL / key findings
No significant toxicities in 3- or 6-month monkey studies; pharmacology-related lower globulin, reduced TDAR, smaller splenic germinal centers, skin erythema
“No significant toxicities were observed in the 3- or 6-month toxicology studies with siltuximab and the toxicokinetic (TK) results indicated that anti-siltuximab antibodies did not interfere with exposure or study results.”
Risksopen answer page →
Immune & cytokine safety
Lower anti-KLH IgM/IgG (TDAR), reduced splenic germinal centers, lower globulin; first-dose infusion reaction (facial swelling) in 1/52 monkeys
“These effects suggest the potential for infection secondary to immune modulation. Although not common, first-dose infusion reaction occurred in a monkey (in 1 out of 52) and included moderate facial swelling.”
Biodistribution & persistence
No unexpected tissue cross-reactivity; expected staining in brain white matter, cerebellum, cornea, spinal cord and peripheral nerve axons
“Expected specific cross-reactivity staining using biotinylated siltuximab was observed in human tissues from the brain white matter and cerebellum, squamous epithelium of the cornea, axons in the gray and white matter of the spinal cord, and axons of peripheral nerves.”
Modality-specific risk
Infection risk from immune modulation (reduced immunoglobulin), including in infants exposed in utero
“Therefore, the infants born to a mother treated with siltuximab may be at increased risk of infections.”
Anti-drug antibodies: animals
ADA in 1 monkey at 9.2 mg/kg in each 3-month study; exposure otherwise extensive in all other animals
“An anti-siltuximab antibody response was detected in one female at 9.2 mg/kg from the 3-month study with siltuximab, and in one male at 9.2 mg/kg from the 3-month combination study with siltuximab and IL-2. With the exception of these 2 animals, toxicokinetic (TK) analysis confirmed extensive systemic exposure in monkeys administered siltuximab”
Anti-drug antibodies: patients
0% (0/243) by EIA and 2% (4/189) by ECLIA; none neutralizing
“Following SYLVANT dosing, 0/243 (0%) patients tested positive for anti-siltuximab antibodies by EIA and 4/189 (2%) patients tested positive by ECLIA. Further immunogenicity analyses were conducted for all positive samples from the 4 patients with detectable anti-siltuximab antibodies. None of these patients had neutralizing antibodies.”
Label warnings
- Concurrent Active Severe Infections
- Vaccinations
- Infusion Related Reactions and Hypersensitivity
- Gastrointestinal Perforation
InfectionsHypersensitivity & infusion reactionsGastrointestinal
US prescribing information, 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 Sylvant 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 significant toxicities in 3- or 6-month monkey studies; pharmacology-related lower globulin, reduced TDAR, smaller splenic germinal centers, skin erythema (FDA pharmacology/toxicology review, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) IV cynomolgus monkey study (T-2003-010) with 3-month recovery
“and a 6-month study followed by a 3-month recovery period (T-2003-010)”
Pivotal GLP studies
Cynomolgus monkey 3- and 6-month studies, weekly IV infusion 9.6 or 46 mg/kg, plus 3-month combination study with IL-2
“Repeat dose toxicology studies of 3-months or 6-months duration with extended recovery periods were conducted using weekly IV infusion administration of 9.6 or 46 mg/kg/dose siltuximab alone or in combination with IL-2 administration.”
DART package
Species: DART
Cynomolgus monkey (EFD) and mouse (male and female fertility, with surrogate CNTO 345)
“The potential developmental and reproductive toxicity of siltuximab was investigated in an embryofetal development study in cynomolgus monkeys (T-205-036). Supportive fertility studies in male (Study T-2010-033) and female (Study T-2010-032) mice were conducted using the rat IgG1 isotype anti-mouse IL-6 mAb CNTO 345.”
Reproductive & developmental
Monkey EFD and ePPND (humanized analog): placental transfer, reduced globulin in dams and offspring; mouse surrogate fertility studies negative
“Siltuximab crossed the placenta and resulted in reduced globulin levels in pregnant animals and in the offspring; this may be secondary to a decreased production of immunoglobulin as expected from the pharmacology of this product.”
PPND / ePPND: when
ePPND in cynomolgus monkey (humanized version of siltuximab): completed before the marketing application
“An embryo-fetal developmental toxicology study was conducted in cynomolgus monkeys with siltuximab and an ePPND study was conducted in the same species with a humanized version of siltuximab.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not needed)
“Genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Carcinogenicity model
Not conducted; weight of evidence suggests low potential, but increased susceptibility to specific tumors not ruled out
“Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.”
Carcinogenicity timing
Not required for this application
“Genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey chronic-study AUC ~7-fold human AUC in cancer patients
“the mean ± SD AUC0-t in monkeys (20264.11 ± 4435.72 μg·day/mL) was approximately 7-fold higher than the mean ± SD AUC0-t value (2800.9 ± 1086.2 μg·day/mL) in cancer patients.”
NOAEL / key findings
No significant toxicities in 3- or 6-month monkey studies; pharmacology-related lower globulin, reduced TDAR, smaller splenic germinal centers, skin erythema
“No significant toxicities were observed in the 3- or 6-month toxicology studies with siltuximab and the toxicokinetic (TK) results indicated that anti-siltuximab antibodies did not interfere with exposure or study results.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of human IL-6-producing tumours (e.g. H460 lung) with siltuximab; no MCD model
“In a study of mice bearing H460 human lung tumour xenografts, twice-weekly dosing with CNTO 328 (25 mg/kg) caused a reduction in tumour volume and a delay in time to tumour endpoint by 7.6 days compared to PBS control.”
Why that model
Siltuximab neutralizes human and primate IL-6 but not mouse or rat IL-6
“Siltuximab binds to and neutralizes human and non-human primate IL-6 but does not inhibit mouse, rat, dog, pig or guinea pig IL-6.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo data sufficient to show anti-tumoral effect; MCD mouse model not necessary
“Available data from in vitro and in vivo studies with siltuximab are considered enough to conclude it has an anti-tumoral effect. Additional in vivo experiments in the mice model for MCD are not considered necessary.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No rodent carcinogenicity study; carcinogenic risk assessed by weight of evidence including murine tumour surveillance studies with surrogate
Why: Data with siltuximab and other IL-6 inhibitors suggest low carcinogenic potential; weight of evidence does not indicate a human risk · Weight of evidence · Class precedent
“Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause carcinogenicity is low.”
“The relevance of the findings to humans is undetermined but the weight of evidence approach used to determine the carcinogenic risk of siltuximab does not indicate a risk for humans.”
DARTAcceptedBeyond the letter
Fertility tested in mice with a rat anti-mouse IL-6 surrogate; ePPND in monkeys with a humanized siltuximab variant
Why: Binding, inhibition and epitope mapping showed the surrogates were suitable surrogates for siltuximab · Pharmacology or kinetics
“A fertility study was conducted with a rat anti-mouse IL6 mAb (CNTO 345) in mice and an enhanced pre- and post-natal development (ePPND) study was conducted with a humanized version of siltuximab (CNTO 136) in cynomolgus monkeys.”
“Studies determining the binding, inhibition, and epitope mapping were performed demonstrating the suitability of CNTO 345 and CNTO 136 for their use as surrogates of siltuximab in toxicology studies.”
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