Spesolimab is a humanised antagonistic monoclonal immunoglobulin G1 (IgG1) antibody blocking human IL36R signalling. Binding of spesolimab to IL36R prevents the subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory pathways.
Following treatment with spesolimab in patients with GPP, reduced levels of C-reactive protein (CRP), IL6, T helper cell (Th1/Th17) mediated cytokines, keratinocyte-mediated inflammation, neutrophilic mediators, and proinflammatory cytokines were observed in serum and skin at week 1 compared to baseline and was 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. In some patients with ADA titer values >4 000, plasma spesolimab concentrations were reduced, with no apparent impact on pharmacokinetics at ADA titers below 4 000.
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 (0.3-20 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. Clearance of spesolimab was increased in some patients with ADA titer values >4 000.
At low doses, spesolimab exhibited target-mediated drug disposition (TMDD) kinetics after single intravenous dose administration. At doses from 0.01 to 0.3 mg/kg, both clearance (CL) and terminal half-life were dose dependent, and systemic exposure (AUC) increased more than dose proportionally with dose. The saturation of the nonlinear elimination pathway occurred at about 0.3 mg/kg as spesolimab AUC increased approximately linearly with dose from 0.3 to 20 mg/kg, and CL and terminal half-life were independent of dose.
Spesolimab concentrations were lower in subjects with higher body weight. The impact of body weight on spesolimab exposure is not expected to be clinically meaningful up to approximately 130 kg. The clinical relevance of higher body weight greater than 130 kg is unknown.
Based on population pharmacokinetic analyses, age, gender and race do not have an 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 has not yet been studied.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
