Spesolimab for the Treatment of Generalized Pustular Psoriasis Flares

March 2025 | Volume 24 | Issue 3 | 242 | Copyright © March 2025


Published online February 28, 2025

doi:10.36849/JDD.8322

Sabine L. Abukhadra BSa, Shirley P. Parraga BSa, Steven R. Feldman MD PhDa-d

aCenter for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC
bDepartment of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC
cDepartment of Social Sciences & Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC
dDepartment of Dermatology, University of Southern Denmark, Odense, Denmark

Abstract
Background: Generalized pustular psoriasis (GPP) is a rare, life-threatening neutrophilic skin condition characterized by widespread sterile eruptions. Treatment approaches vary due to a lack of standardized guidelines. Interleukin-36 signaling is involved in GPP activation and disease progression. An interleukin-36 receptor monoclonal antibody, spesolimab, is a new treatment option for GPP flares. The Effisayil 1 clinical trial investigated the efficacy and safety of spesolimab, a remarkable task due to the unpredictable nature of GPP flares coupled with intrinsic trial challenges.
Methods: We searched PubMed using the terms: generalized pustular psoriasis, spesolimab, and Effisayil 1. Clinicaltrials.gov was used to identify clinical trial data including efficacy, safety, and tolerability.
Results: In Effisayil 1, a phase II study, 53 patients with a GPP flare were enrolled: 35 patients were randomized to spesolimab and 18 to placebo. At baseline, 46% of the patients in the spesolimab group and 39% of the patients in the placebo group had a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 3; 37% and 33% of patients in each group, respectively, had a pustulation subscore 4. At the end of week 1, 19 of the patients in the spesolimab group, (54.3%) had a pustulation subscore of 0 compared to 1 patient in the placebo group (5.6%) (-49%, P<0.001).
Conclusions: The Effisayil 1 trial faced many difficulties affecting trial completion, but the results of this study provided encouraging results. Spesolimab was effective in treating GPP flares after just one week. Patient demographics and baseline characteristics did not affect the efficacy or safety profile of spesolimab.

J Drugs Dermatol. 2025;24(3):242-245. doi:10.36849/JDD.8322

INTRODUCTION

Generalized pustular psoriasis (GPP) is a rare skin condition with prevalence rates ranging from 2 to 124 cases per million persons characterized by potentially disfiguring and painful erythematous, exudate-filled lesions.1,2 Interleukin 36 (IL-36) plays a key role in GPP; some patients with GPP have a recessive mutation in the interleukin 36 receptor antagonist (IL-36RN) gene. The IL-36RN gene antagonizes IL-1F6, IL-1F8, and IL-1F9, cytokines that activate pro-inflammatory pathways. Various substitution, frameshift, and splicing defect mutations have been implicated in the pathophysiology of GPP, including an autosomal recessive homozygous missense mutation causing the substitution of proline for leucine at amino acid 27 in multiple families.3 Families who lack IL-36RA have unrelenting disease.1

The IL-36 pathway plays a role in acute generalized exanthematous pustulosis (AGEP), too. AGEP presents as erythematous, painful pustules that appear as a reaction to infection or medication.4 In contrast, psoriasis vulgaris is associated with over 100 genetic loci and HLA genes with the IL-23/TYK2/IL-17 inflammatory pathway playing the key role.6 

Treatment of GPP is vital to address the severity of symptoms and mortality risk, but because it is so rare, it is seldom a focus of research. With a better understanding of the pathophysiology of GPP, spesolimab was developed to inhibit the IL-36R, replacing the role of the IL-36RA (Figure 1). While it is challenging to do a controlled clinical trial for such a rare, severe disease, the Effisayil trial was established to test the efficacy and safety of spesolimab for GPP.

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