Generalized pustular psoriasis (GPP) is a rare, life-threatening disease, characterised by recurrent flares of pustular, erythematous rashes, with a strong genetic linkage to the IL-36 pathway. The efficacy and safety of a single, open-label, intravenous dose of spesolimab (BI 655130; 10 mg/kg), an anti-IL-36R monoclonal antibody, was assessed in a Phase I trial (NCT02978690) in 7 patients presenting with a moderate-to-severe GPP flare. To characterise the molecular response to spesolimab, biomarkers in lesional skin and blood were analysed. Spesolimab treatment resulted in all patients achieving a GPP Physician Global Assessment (GPPGA) score of 0 or 1 by Week 4. In lesional skin, improvement in GPPGA score was accompanied by a strong downregulation of genes associated with the IL-36 family (IL36G, IL36A), innate immune response (TNF, IL1B, IL6), Th1/Th17-mediated inflammation (IL12B, IL23, IL17C, IL22) and neutrophil attractant pathways (CXCL1/2/3/5/6/8, NCF1/2/4, ELANE). In blood, pro-inflammatory genes involved in neutrophil activation (IL1B, CD177, S100A8/9, S100A12, MMP9, MMP25) were strongly downregulated after spesolimab treatment; these changes were accompanied by reductions in blood protein expression (IL-6, CRP, CXCL1, IL1RN, CCL20). mRNA and protein reduction were observed as early as Day 7 after spesolimab treatment and maintained through Week 4. Overall, in addition to clinical improvements, inhibition of IL-36R with spesolimab was associated with strong downregulation of neutrophil-focused pathogenic pathways in lesional skin and blood of GPP patients.

Generalized pustular psoriasis (GPP) is a rare, life-threatening disease, characterized by recurrent flares of pustular, erythematous rashes, with a strong genetic linkage to the IL-36 pathway. The efficacy and safety of a single, open-label, intravenous dose of BI 655130 (10 mg/kg), an anti-IL-36R monoclonal antibody, was assessed in a Phase I trial (NCT02978690) in 7 patients presenting with a moderate-to-severe GPP flare. To characterize the response to BI 655130 at a molecular level, biomarkers in lesional skin and blood were analyzed. BI 655130 treatment resulted in all patients achieving a GPP Physician Global Assessment (GPPGA) score of 0 or 1 by Week 4. In lesional skin, improvement in GPPGA score was accompanied by strong downregulation of genes associated with the IL-36 family (IL36G, IL36A), innate immune response (TNF, IL1B, IL6), Th1/Th17 mediated inflammation (IL12B, IL23, IL17C, IL22), and neutrophil attractant pathways (CXCL-1/-2/-3/-5/-6/-8, NCF-1/-2/-4, ELANE). In blood, pro-inflammatory genes involved in neutrophil activation (IL1B, CD177, S100A8/9, S100A12, MMP9, MMP25) were strongly downregulated after BI 655130 treatment. These changes were accompanied by reductions in select blood proteins (IL-6, CRP, CXCL1, IL1RN, CCL20). mRNA and protein reduction was observed as early as Day 7 after BI 655130 treatment and maintained through Week 4. Overall, in addition to clinical improvements, BI 655130 inhibition of IL-36R signaling was associated with strong downregulation of neutrophil focused pathogenic pathways in skin and blood of GPP patients.