Spevigo
spesolimab
Species
Mouse
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
Mouse (surrogate antibody) only
“Spesolimab does not bind to IL36R in common nonclinical species. Therefore, BI 674304, a surrogate monoclonal antibody that specifically binds to mouse IL36R was developed to assess the pharmacology and toxicology of IL36R inactivation in mice.”
Why that species
No binding to mouse, rat, minipig, rhesus, marmoset or hamster IL-36R; very low affinity and poor potency in cynomolgus monkey
“spesolimab did not bind to IL36R from the mouse, mini pig, rhesus money, marmoset, rat, or hamster, and had very low affinity to IL36R from cynomolgus monkey.”
Surrogate molecule
Yes: rat-mouse chimeric anti-mouse receptor antibody BI 674304, used for repeat-dose toxicity and DART studies in mice
“BI 674304 was evaluated in a battery of nonclinical studies that included evaluation of PK, immunotoxicity, repeat-dose toxicity, and reproductive and developmental toxicology.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“BI 674304 was evaluated in a pivotal 26-week repeat-dose general toxicity study in CD-1 mice.”
Pivotal GLP studies
26-week CD-1 mouse study with surrogate BI 674304, IV twice weekly at 10 and 50 mg/kg
“BI 674304 was evaluated in a pivotal 26-week repeat-dose general toxicity study in CD-1 mice. BI 674304 was administered via intravenous injection, twice weekly, at the doses of 0, 10, and 50 mg/kg.”
Route in tox
Intravenous
“BI 674304 was administered via intravenous injection, twice weekly, at the doses of 0, 10, and 50 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Genotoxicity and stand-alone safety pharmacology studies were not conducted.”
Carcinogenicity
Not conducted; weight-of-evidence (chronic surrogate study, literature, clinical data) found no concrete reason for concern; ECAC concurred
“there are no concrete reasons to believe that inhibition of IL36R by spesolimab would lead to carcinogenicity. The Executive Carcinogenicity Assessment committee (ECAC) concurred with this conclusion.”
Reproductive & developmental
Mouse FEED, EFD and PPND with surrogate (up to 50 mg/kg): no adverse effects on fertility, embryofetal or postnatal development
“The maternal and developmental NOAELs were both 50 mg/kg/dose.”
Safety pharmacology
No stand-alone or embedded studies; no respiratory or neurobehavioral signs in mouse studies up to 26 weeks
“However, no treatment-related organ toxicities or clinical signs indicative of respiratory or neurobehavioral effects were observed in mice after intravenous administration of the surrogate antibody BI 674304 for up to 26 weeks”
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 Spevigo 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: NOAEL 50 mg/kg/dose (highest dose) in 6-month mouse surrogate study; no mortality, clinical signs, or gross/histopathology findings (FDA multi-discipline review, p. 37)
NOAEL / key findings
NOAEL 50 mg/kg/dose (highest dose) in 6-month mouse surrogate study; no mortality, clinical signs, or gross/histopathology findings
“The NOAEL for the 6-month toxicity study was the highest dose 50 mg/kg/dose.”
Risksopen answer page →
Immune & cytokine safety
Human whole-blood cytokine release assay: no IL-2, IL-6, TNF-α or IFN-γ release; low cytokine release potential
“No specific IL-2, IL-6, TNF-α, or IFN-γ release was observed.”
Biodistribution & persistence
Human TCR: expected staining of lymphocytes and epithelial cells consistent with IL-36R expression; no tissue distribution studies
“Spesolimab stained lymphocytes in tonsil epithelial cells in a variety of tissues, which was considered expected based on previous data and literature on IL-36R expression.”
Modality-specific risk
Infection risk (IL-36 pathway in epithelial host defence) and potential reduced cancer immunosurveillance
“Given the expression of the IL36R in epithelium of various tissues including skin and lung, and as the IL36 pathway has been implicated in host-defence, spesolimab treatment may be expected to increase the risk for serious, severe or opportunistic infections.”