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.”
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.”
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 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 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.”