Spesolimab, an Anti-Interleukin-36 Receptor Antibody, in Patients with Palmoplantar Pustulosis: Results of a Phase IIa, Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Study

Abstract

Introduction: Palmoplantar pustulosis (PPP) is a chronic, inflammatory skin disease, with high disease burden, that is often refractory to treatment. There is a high unmet clinical need for the treatment of patients with PPP. The objectives of this study were to evaluate the safety and efficacy of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients with PPP.

Methods: This was a phase IIa, multicenter, double-blind, randomized, placebo-controlled pilot study comparing 900 mg spesolimab (n = 19), 300 mg spesolimab (n = 19), and placebo (n = 21) administered intravenously every 4 weeks until week 12 in patients with PPP. The primary efficacy endpoint was the achievement of Palmoplantar Pustulosis Area and Severity Index 50 (PPP ASI50) at week 16, defined as achieving an ≥ 50% decrease from baseline PPP ASI.

Results: At week 16, 31.6% of patients in both spesolimab dose groups achieved PPP ASI50 versus 23.8% receiving placebo (risk difference 0.078; 95% confidence interval -0.190, 0.338). Thus, the primary endpoint was not met. Spesolimab was well tolerated with no clinically relevant treatment-emergent safety signals observed.

Conclusions: PPP severity declined over time in all treatment groups after the start of treatment, with a faster decline in the spesolimab arms than in the placebo arm, indicating a potential treatment effect for spesolimab. Limitations to the study included a small sample size and lower overall disease severity than expected at baseline. It is possible that the primary efficacy endpoint may have coincided with natural disease resolution in some patients. Further effects of the efficacy of spesolimab in PPP are being explored in a phase IIb trial.

Keywords: BI 655130; IL-36; IL-36R; PPP; biomarkers; palmoplantar pustular psoriasis; palmoplantar pustulosis; randomized controlled trial; spesolimab.

Fig. 1

Study disposition. *Last treatment administered at visit 10 (week 12). ^†From the end of treatment until visit 13 (end of trial)

Fig. 2

Mean (95% CI) percent change from baseline in PPP ASI over time in (i) all patients and (ii) patients with no improvement in PPP ASI from screening to baseline (screening < 1.2 × baseline). Panel (i) shows the mean (95% CI) percent change from baseline in PPP ASI over time in all patients, represented as negative percent change from baseline. The full analysis set was used. Observed cases were used without imputation of missing data. All values after intake of medication are excluded. Panel (ii) shows mean (95% CI) change from baseline in PPP ASI in patients with no improvement in PPP ASI from screening to baseline: four patients in the placebo group, one in the spesolimab 300 mg group, and three in the spesolimab 900 mg group were not included in this analysis. The full analysis set was used. The last observation carried forward method was used to impute missing data. CI confidence interval, PPP ASI Palmoplantar Pustular Psoriasis Area and Severity Index

Fig. 3

Mean (90% CI) percent change from baseline in PPP ASI over time in patients with PPP ASI above the median (16.7) at baseline. Full analysis set, last observation carried forward. CI confidence interval, PPP ASI Palmoplantar Pustular Psoriasis Area and Severity Index

Fig. 4

Mean (95% CI) percent change in pustular severity over time in patients with PPP ASI above the median (16.7) at baseline. Full analysis set, last observation carried forward. CI confidence interval, PPP ASI Palmoplantar Pustular Psoriasis Area and Severity Index

Fig. 5

Lesional biomarker analysis comparing gene expression levels in patients (n = 23) with a PPP ASI above/below the median (16.7) at baseline. Lesional biomarker analysis of IL-36 pathway genes was measured by RNA sequencing to compare differences in gene expression in patients with a PPP ASI above or below the median (16.7) at baseline prior to spesolimab treatment. Biomarker samples were collected prior to infusion at the infusion visit. Box plot denotes IQR, with bars representing the minimum and maximum values within 1.5 × IQR. Individual values are denoted by circles (green), and mean values are denoted by diamonds (gray). Baseline biomarker levels could not be determined for one patient with PPP ASI below the median at baseline for the analysis of IL36G or IL36RN; therefore, this patient was excluded from analysis for these genes. IL interleukin, IQR interquartile range, PPP ASI Palmoplantar Pustular Psoriasis Area and Severity Index