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.”
Species: general tox
Mouse (CD-1) with surrogate anti-mouse IL36R antibody BI 674304
“BI 674304 was evaluated in a pivotal 26-week repeat-dose general toxicity study in CD-1 mice.”
Species: DART
Mouse (full DART programme) with surrogate BI 674304
“A full Developmental and reproductive toxicology (DART) programme was performed with BI 674304.”
Species: carcinogenicity
Not conducted; weight-of-evidence from chronic surrogate mouse data, literature and clinical data
“Carcinogenicity was assessed based on data from chronic dosing of BI 674304 in mice, scientific literature on the potential role of IL36R in tumor promotion, and clinical data from spesolimab clinical trials.”
Surrogate used in
Yes: mouse-specific anti-IL36R surrogate BI 674304 for PK, immunotoxicity, repeat-dose and DART studies
“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”
Genotox: Ames
Not conducted (monoclonal antibody)
“No genotoxicity studies have been performed with spesolimab. This is considered acceptable as monoclonal antibodies are unlikely to interact directly with DNA or other chromosomal material (see SmPC section 5.3).”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody)
“No genotoxicity studies have been performed with spesolimab. This is considered acceptable as monoclonal antibodies are unlikely to interact directly with DNA or other chromosomal material (see SmPC section 5.3).”
Genotox: in vivo
Not conducted (monoclonal antibody)
“No genotoxicity studies have been performed with spesolimab. This is considered acceptable as monoclonal antibodies are unlikely to interact directly with DNA or other chromosomal material (see SmPC section 5.3).”
Carcinogenicity model
Not conducted; weight-of-evidence (6-month surrogate mouse study, literature, clinical data)
“Regarding carcinogenesis, based on data from the 6-month general toxicity study of BI 674304 in mice, scientific literature on the potential role of IL36R in tumor promotion, and clinical data from spesolimab clinical trials, there are no concrete reasons to believe that inhibition of IL36R by spesolimab would lead to carcinogenicity.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, 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.”
hERG / QT
Not conducted; no stand-alone or embedded safety pharmacology studies
“Stand-alone safety pharmacology studies were not conducted. Safety pharmacology studies were not embedded in the repeat-dose toxicity 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 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
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/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.”
Anti-drug antibodies: animals
26-week mouse surrogate study: ADA in 4 of 17 samples (10 mg/kg/dose) and 3 of 23 (50 mg/kg/dose)
“Anti-drug antibody (ADA) was detected in 4 of 17 samples at 10 mg/kg/dose and 3 of 23 samples at 50 mg/kg/dose.”
Anti-drug antibodies: patients
GPP (IV): ADA in 46% by Week 12-17; 24% had titers >4000 with decreased exposure
“In GPP patients treated with IV spesolimab, anti-drug antibodies (ADAs) were formed in 46% of patients by Week 12-17 with a median onset of 2.3 weeks. Among ADA-postitive patients, those with ADA titer values greater than 4000 (24%), were observed to have significantly decreased plasma spesolimab concentrations from Week 3 onward.”
Label warnings
- Infections
- Risk of Tuberculosis
- Hypersensitivity and Infusion-Related Reactions
- Vaccinations
InfectionsHypersensitivity & infusion reactions
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 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
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/dose (highest dose) in 6-month mouse surrogate study; no mortality, clinical signs, or gross/histopathology findings (FDA multi-discipline review, p. 37)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV mouse study with surrogate antibody BI 674304, with 4-week recovery
“BI 674304: 26-Week (Twice Weekly) Intravenous Injection Toxicity Study in the Mouse with a 4-Week Recovery Period/ 16R072”
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.”
DART package
Species: DART
Mouse (full DART programme) with surrogate BI 674304
“A full Developmental and reproductive toxicology (DART) programme was performed with BI 674304.”
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.”
PPND / ePPND: when
PPND in mouse with surrogate antibody BI 674304: completed before the marketing application
“In a mouse pre- and postnatal developmental study, BI 674304 (0, 10, and 50 mg/kg/dose, twice weekly) was administered via intravenous injection starting on gestation day 6 through lactation day 18.”
Carcinogenicity
Species: carcinogenicity
Not conducted; weight-of-evidence from chronic surrogate mouse data, literature and clinical data
“Carcinogenicity was assessed based on data from chronic dosing of BI 674304 in mice, scientific literature on the potential role of IL36R in tumor promotion, and clinical data from spesolimab clinical trials.”
Carcinogenicity model
Not conducted; weight-of-evidence (6-month surrogate mouse study, literature, clinical data)
“Regarding carcinogenesis, based on data from the 6-month general toxicity study of BI 674304 in mice, scientific literature on the potential role of IL36R in tumor promotion, and clinical data from spesolimab clinical trials, there are no concrete reasons to believe that inhibition of IL36R by spesolimab would lead to carcinogenicity.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, 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.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin to clinical exposure calculated for the surrogate antibody
“As no margins to clinical exposure has been calculated for the surrogate antibody, Cmax at NOAEL in the 4-week study was compared to the IC90 of NF-kB inhibition in primary mouse dermal fibroblasts.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Surrogate BI 674304 in imiquimod-induced and IL-36-induced mouse skin inflammation models
“In vivo, BI 674304 reduced Imiquimod-induced skin inflammation in mice. BI 674304 also reduced IL-36-induced skin inflammation and IL-33 production in the skin of mice.”
Why that model
Spesolimab does not bind IL36R in common nonclinical species
“Spesolimab does not bind to IL36R in common nonclinical species.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo proof of concept and mode of action established and supported
“Overall, in vitro and in vivo proof of concept and mode of action of spesolimab in relation to the treatment of flares in adult patients with generalised pustular psoriasis was established and is supported.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No pharmacologically relevant species; repeat-dose and DART toxicology done only with a mouse-specific surrogate antibody (BI674304)
Why: Surrogate shows binding and functional activity comparable to spesolimab · No relevant species · Pharmacology or kinetics
“Given that spesolimab and its surrogate BI674304 show comparable binding and functional activity, the use of BI674304 as a suitable surrogate to evaluate potential effects of IL36 antagonism in toxicology studies mice is agreed. This strategy was also endorsed by CHMP.”
Safety marginAcceptedBeyond the letter
No exposure margins to clinical exposure calculable for the surrogate; NOAEL exposures compared with in vitro IC90 values instead
Why: Toxicology study exposures exceeded the surrogate's IC90 values in primary mouse cells · Pharmacology or kinetics
“Further, based on IC90-values of BI674304 to inhibit mouse IL36α, β or γ-induced IL-2 and IFNγ cytokine production or NFκB phosphorylation in primary mouse cells (3.8-18 nM corresponding to 0.57-2.68 µg/mL), the exposures in the toxicology studies were higher. Thus, sufficient exposures have been reached in the studies.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; weight-of-evidence assessment instead
Why: Not active in rodents; 6-month surrogate study, literature on IL36R and clinical data give no reason for concern · No relevant species · Weight of evidence
“Spesolimab is not pharmacologically active in rodents (or any other relevant species) why no meaningful data would be generated in long-term carcinogenicity studies. Therefore, an evaluation of the potential carcinogenicity risk of spesolimab has been performed using a weight-of-evidence (WoE) approach.”
“Regarding carcinogenesis, based on data from the 6-month general toxicity study of BI 674304 in mice, scientific literature on the potential role of IL36R in tumor promotion, and clinical data from spesolimab clinical trials, 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.”
Safety pharmacologyVerdict not stated
No stand-alone safety pharmacology studies and no safety pharmacology endpoints embedded in repeat-dose studies
Why: No respiratory or neurobehavioral signs in mouse toxicity studies
“Stand-alone safety pharmacology studies were not conducted. Safety pharmacology studies were not embedded in the repeat-dose toxicity studies. However, no treatment-related organ toxicities or clinical signs indicative of respiratory or neurobehavioral effects were observed in mice”
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