Spesolimab is a humanised antagonistic monoclonal immunoglobulin G1 (IgG1) antibody blocking human interleukin 36 receptor (IL36R) signalling. Binding of spesolimab to IL36R prevents the subsequent activation of IL36R by its ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory pathways.
Following treatment with intravenous spesolimab in patients with GPP, reduced levels of C-reactive protein (CRP), IL6, T helper cell (Th1/Th17) mediated cytokines, keratinocyte-mediated inflammation markers, neutrophilic mediators, and proinflammatory cytokines were observed in serum and skin at week 1 compared to baseline and were associated with a decrease in clinical severity. These reductions in biomarkers became more pronounced at the last measurement at week 8 in Effisayil 1.
A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP and patients with other diseases. After a single intravenous dose of 900 mg, the population PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical ADA-negative patient with GPP were 4 750 (4 510, 4 970) μg·day/mL and 238 (218, 256) μg/mL, respectively. After a 600 mg subcutaneous loading dose of spesolimab followed by 300 mg spesolimab subcutaneously every 4 weeks, the mean (CV%) steady-state trough concentration ranged from 33.4 μg/mL (37.6%) to 42.3 μg/mL (43.0%).
Following subcutaneous single dose administration of spesolimab in healthy volunteers, peak plasma concentrations were achieved between 5.5 to 7.0 days after dosing. After subcutaneous administration in the abdomen, absolute bioavailability was slightly higher at higher doses with estimated values of 58%, 65%, and 72% at 150 mg, 300 mg, and 600 mg, respectively. Based on limited data, absolute bioavailability in the thigh was approximately 85% following a subcutaneous dose of 300 mg spesolimab.
Based on the population pharmacokinetic analysis, the typical volume of distribution at steady state was 6.4 L.
The metabolic pathway of spesolimab has not been characterised. As a humanised IgG1 monoclonal antibody, spesolimab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab clearance (95% CI) in a typical ADA-negative patient with GPP, weighing 70 kg was 0.184 L/day. The terminal-half-life was 25.5 days.
When administered intravenously, spesolimab exhibited linear pharmacokinetics with dose-proportional increase in exposure across single dose ranges of 0.3 to 20 mg/kg. Both clearance (CL) and terminal half-life were independent of dose. Following subcutaneous single dose administration, spesolimab exposure increased slightly more than dose-proportionally across the dose range of 150 mg to 600 mg due to slightly increased bioavailability at higher doses.
Spesolimab concentrations were lower in subjects with higher body weight and higher in subjects with lower body weight. Spesolimab has not been studied in patients with GPP weighing more than 164 kg. Based on pharmacokinetic modelling and simulation, the recommended dose for adolescents from 12 years of age weighing ≥30 and <40 kg is half the recommended dose than for adults and adolescents from 12 years of age and weighing at least 40 kg.
The exposure in patients weighing ≥30 and <40 kg receiving the reduced dosing regimen is expected to be comparable with those observed in GPP studies.
Based on population pharmacokinetic analyses, age, gender and race do not have a clinically relevant effect on the pharmacokinetics of spesolimab.
As a monoclonal antibody, spesolimab is not expected to undergo hepatic or renal elimination. No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab was conducted.
Population PK analysis did not identify mild hepatic impairment or mild or moderate renal impairment as having an influence on the systemic exposure of spesolimab.
The pharmacokinetics of spesolimab in paediatric patients below the age of 14 years have not been studied.
The plasma pharmacokinetics of spesolimab observed in adolescents were consistent with that observed in adults.
Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies.
Non-clinical studies conducted in mice using a surrogate antibody directed towards murine IL36R do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development or fertility.
Genotoxicity studies have not been conducted with spesolimab.
Carcinogenicity and mutagenicity studies have not been conducted with spesolimab.
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