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Commentary on a Clinical Trial of Spesolimab, a Humanized Anti-interleukin-36 Receptor Monoclonal Antibody, in Generalized Pustular Psoriasis.

ABSTRACT: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening autoinflammatory skin disease, mainly mediated by the interleukin (IL)-36 signaling pathway. The irregular and relapsing pattern of the skin symptoms, the GPP-associated complications, as well as the physical pain caused by the disease add burdens to patients with GPP. Currently, spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, has been approved as a GPP-specific treatment targeting IL-36 signaling. Effisayil 1, a randomized, controlled clinical trial, investigated the efficacy and safety of spesolimab in patients presenting with a GPP flare. In this commentary, we discuss the study design, endpoints, and clinical outcomes of Effisayil 1, which differed from previous clinical trials that investigated other biologic agents (adalimumab, secukinumab, brodalumab, ixekizumab, and guselkumab) in patients with GPP.

SUBMITTER: Shao S

PROVIDER: S-EPMC9674804 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Commentary on a Clinical Trial of Spesolimab, a Humanized Anti-interleukin-36 Receptor Monoclonal Antibody, in Generalized Pustular Psoriasis.

Shao Shuai S Wang Gang G

Dermatology and therapy 20221008 12

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening autoinflammatory skin disease, mainly mediated by the interleukin (IL)-36 signaling pathway. The irregular and relapsing pattern of the skin symptoms, the GPP-associated complications, as well as the physical pain caused by the disease add burdens to patients with GPP. Currently, spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, has been approved as a GPP-specific treatment targeting IL-36 sig ...[more]

PMID: 36208408

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Project description:Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening inflammatory disease, characterized by the rapid and widespread eruption of small, sterile pustules with surrounding skin erythema. Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target. Spesolimab is a first-in-class humanized monoclonal antibody that binds specifically to the IL-36 receptor, and antagonizes IL-36 signaling. Spesolimab obtained regulatory approval in the United States (US) in September 2022 for use in the treatment of GPP flares in adults, and was subsequently approved for GPP flare treatment in many other countries across the world. Recently, regulatory approval was granted for subcutaneous dosing of spesolimab for treatment of GPP when not experiencing a flare. Here, we review data from two key clinical trials that supported the initial US regulatory approval; namely, the phase 1 proof-of-concept trial (ClinicalTrials.gov ID, NCT02978690), and Effisayil™ 1 (NCT03782792), which remains the largest and only randomized clinical trial in patients experiencing GPP flares published to date. In the phase 1 proof-of-concept trial, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) was attained in 5/7 (71%) patients by week 1 and in all 7 patients by week 4; and the mean percent improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score from baseline was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. In Effisayil™ 1, a GPPGA pustulation subscore of 0 (no visible pustules) was achieved in 19/35 (54%) patients receiving spesolimab at the end of week 1, versus 1/18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001); and a GPPGA total score of 0 or 1 was achieved by 15/35 (43%) patients in the spesolimab group, versus 2/18 (11%) patients in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Infections at week 1 were reported in 6/35 (17%) patients receiving spesolimab and in 1/18 (6%) patients receiving placebo. These data demonstrate the efficacy and safety of spesolimab in providing rapid and sustained clinical improvement for patients with GPP flares, which translates into improved quality of life, by offering a targeted therapy for GPP.

Project description:BackgroundGeneralized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes.MethodsTo conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP.ResultsA total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27).ConclusionThe IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.

Project description:IntroductionGeneralized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease. The global Effisayil 1 study investigated the efficacy and safety of spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, in patients experiencing GPP flare. This analysis aimed to explore the efficacy and safety of spesolimab in the Chinese subgroup of Effisayil 1.MethodsEffisayil 1 was a multicenter, randomized, double-blind, placebo-controlled phase II study. Eligible patients with a GPP flare were randomly assigned (2:1) to receive a single intravenous dose of spesolimab (900 mg) or placebo on day 1. On day 8, patients who had persistent symptoms that met a predefined criterion could receive open-label spesolimab. After day 8, patients with recurrent flares following clinical response could receive rescue treatment with open-label spesolimab. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 at week 1. The key secondary end point was a GPPGA total score of 0 or 1 at week 1.ResultsEleven Chinese patients were randomized, with five patients receiving spesolimab and six receiving placebo. At week 1, 60.0% (3/5) of patients in the spesolimab group and 16.7% (1/6) of patients in the placebo group achieved a GPPGA pustulation sub-score of 0 (risk difference 43.3%; 95% CI -22.6, 86.2); 60.0% and 16.7% of patients in the spesolimab and placebo group, respectively, achieved a GPPGA total score 0 or 1 (risk difference 43.3%; 95% CI -22.6, 86.2). Overall, four patients in each group of the spesolimab and the placebo groups reported at least one adverse event (AE) by week 1, with two and three reporting drug-related AEs, respectively. One patient reported a serious AE that was not considered to be drug related. No death occurred during the study period.ConclusionIn the Chinese subgroup of the Effisayil 1 study, more patients receiving spesolimab experienced lesion clearance than those on placebo at week 1, with an acceptable safety profile that was consistent with the global study population.Trial registrationNCT03782792.

Dataset Information

Commentary on a Clinical Trial of Spesolimab, a Humanized Anti-interleukin-36 Receptor Monoclonal Antibody, in Generalized Pustular Psoriasis.

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Commentary on a Clinical Trial of Spesolimab, a Humanized Anti-interleukin-36 Receptor Monoclonal Antibody, in Generalized Pustular Psoriasis.

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