FormalPara Key Summary Points

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease. The prevalence of the disease varies across different populations globally; a crude prevalence of 14 cases/million persons was reported in China, and 1.76 cases/million persons in France.

Conventional psoriasis treatments, such as acitretin, methotrexate, and cyclosporine; as well as biologics have been used for patients with GPP; however, GPP-specific treatments that can act fast and have long-lasting effects are still lacking.

Spesolimab, a humanized monoclonal antibody targeting the interleukin-36 receptor, has been approved for the treatment of GPP flares in adult patients; it is the first GPP-specific therapy approved. The phase II study, Effisayil 1, showed that spesolimab rapidly cleared pustules at week 1 after treatment in patients with GPP flares, compared with those in the placebo group.

The current analysis showed that more Chinese patients who received spesolimab in the Effisayil 1 trial had lesion clearance than those on placebo at week 1, with an acceptable safety profile. The results are consistent with the global population in the Effisayil 1 trial.

The results of this subgroup analysis of the Chinese population are encouraging and warrant further investigation on a larger scale for Chinese patients presenting GPP flares who can benefit from spesolimab.

Introduction

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease, characterized by irregular, acute and recurrent flares of sterile pustules, with or without systemic inflammation [1, 2]. The prevalence of the disease varies across geographical regions globally, with a reported 88–124 cases/million persons in South Korea, 7.46 cases/million persons in Japan, and 1.76 cases/million persons in France [3,4,5]. A recent study in China reported a crude prevalence of 14 cases/million persons in 2016 [6].

The pathogenesis of GPP involves various proinflammatory cytokines, including interleukin (IL)-1, IL-17A, IL-36, IL-22, tumor necrosis factor (TNF)-α and interferon-γ [7], among which, IL-36 plays the most prominent role. IL-36 cytokines (IL-36α, IL-36β, IL-36γ) and IL-36 receptor antagonist (IL-36Ra) are expressed in various cell types, including keratinocytes, and damaged skin activates keratinocytes to release IL-36 [1, 8]. Binding of IL-36 cytokines to IL-36R activates the IL-36 signaling pathway, leading to the local and systemic inflammatory responses seen in patients with GPP [1]. Binding of IL-36Ra to IL-36R inhibits the IL-36 signaling pathway. Overexpression of IL-36 or loss-of-function mutation in IL36RN that encodes IL-36Ra results in IL-36Ra dysfunction and, subsequently, enhances the IL-36 pathway and inflammatory responses [1, 9]. Individuals with GPP and loss-of-function mutation in IL36RN showed notably stronger inflammatory responses than those without the mutation [9].

Treatments used for GPP flares are limited [10]. Conventional psoriasis treatments, such as cyclosporine, acitretin, and methotrexate, are generally used to treat GPP globally [11]; in China, only acitretin has been approved for pustular psoriasis [12]. Biologic agents for the treatment of GPP have been approved in Japan, Taiwan, and Thailand, including TNF-α inhibitors, IL-17/IL-17 receptor inhibitors, and IL-23 inhibitors [10, 13, 14]. However, these approvals were based on case reports and open-label, single-arm trials with small sample sizes [1]; for instance, the biologic agents approved in Japan were based on prospective, open-label, single-arm trials that enrolled a maximum of 12 GPP patients with an undefined baseline [10, 15, 16]. There is an unmet need for treatments that can act rapidly and improve clinical outcomes in patients, with favorable safety profiles [1]. Until now, spesolimab, a humanized monoclonal antibody targeting IL-36R [17], has been approved for the treatment of GPP flares in adults; it is the first therapy approved specifically for treating GPP flares.

In a previous phase I proof-of-concept study involving seven patients with GPP, spesolimab was observed to be efficacious in patients who had a GPP flare that covered at least 10% of the body surface area with erythema and pustules [18]. Effisayil 1, a multinational, multicenter, randomized, placebo-controlled phase II study, showed that adult patients with GPP who received spesolimab achieved rapid pustule clearance at week 1, compared with those in the placebo group. Overall, 54% (19/35) of patients in the spesolimab group reported a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA)[19] pustulation sub-score of 0 at week 1, versus 6% (1/18) of patients in the placebo group; 43% (15/35) of patients in the spesolimab group had a GPPGA total score of 0 or 1 at week 1, versus 11% (2/18) in the placebo group. Spesolimab was found to be associated with nonserious infections and systemic drug reactions in patients with GPP, and its safety profile was acceptable [20].

This subgroup analysis aimed to explore the efficacy and safety of spesolimab in Chinese patients who participated in the global Effisayil 1 trial.

Methods

Study Population

Patients aged 18–75 years at screening who were experiencing a GPP flare of moderate-to-severe intensity at randomization, with a GPPGA score ≥ 3, new appearance or worsening of existing pustules, a GPPGA pustulation sub-score ≥ 2, and ≥ 5% body surface area covered with erythema and the presence of pustules, were eligible to enter the study. The key exclusion criteria included: synovitis–acne–pustulosis–hyperostosis–osteitis syndrome; primary erythrodermic psoriasis vulgaris; primary plaque psoriasis vulgaris without pustules or with pustules restricted to psoriatic plaques; drug-triggered acute generalized exanthematous pustulosis; immediate life-threatening flare of GPP requiring intensive care treatment; increased risk of infectious complications; relevant chronic or acute infections including HIV or viral hepatitis; active or latent tuberculosis; treatment with any restricted medications or any drugs considered likely to interfere with the safe conduct of the study, or any prior exposure to an IL-36R inhibitor. In addition, the mutation status of the three main GPP-associated genes (IL36RN, CARD14, AP1S3) was evaluated in patients’ blood samples at baseline, but patients were enrolled in the study regardless of IL36RN mutation status. Further details on the study design, including other inclusion and exclusion criteria, are provided in the protocol and have been published previously [21].

Ethical Approval

The study was performed in compliance with the clinical trial protocol that was reviewed and approved by the Independent Ethics Committees and/or Institutional Review Boards (IECs/IRBs) of the participating centers, in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization of Good Clinical Practice. All patients provided written informed consent. All authors received consent to participate in and publish the study.

Study Design

Effisayil 1 was a multicenter, randomized, double-blind, placebo-controlled phase II study; the study design has been previously described (shown in Fig. 1) [21]. Five centers in mainland China and one center in Taiwan participated in the study. Briefly, patients with a GPP flare were randomly assigned in a 2:1 ratio to receive a single intravenous dose of spesolimab (900 mg) or placebo on day 1. Patients who experienced disease worsening were allowed to receive escape treatment with standard-of-care treatment (according to the treating physician’s choice) between day 2 and day 7. On day 8, patients who had not received escape treatment and had a GPPGA total score ≥ 2 and a GPPGA pustulation sub-score ≥ 2, were eligible to receive open-label spesolimab (a single dose of 900 mg). After day 8, patients who experienced recurrence of flares (defined as an increase of ≥ 2 points in both the GPPGA total score and the pustulation sub-score after a GPPGA total score of 0 or 1 had been achieved) could receive rescue treatment with open-label spesolimab (a single dose of 900 mg). Patients who experienced disease worsening, and who were eligible for rescue treatment with open-label spesolimab after day 8, were allowed to receive the standard of care as escape treatment (according to the treating physician’s choice). Any subsequent flares were treated by using standard-of-care escape therapy. Patients who experienced clinical improvements and completed the trial without flare symptoms were eligible to enter a 5-year open-label extension trial (Effisayil ON, NCT03886246).

Fig. 1
figure 1

Study design. The figure is adapted from Bachelez et al. [20]. *Both GPPGA total score and GPPGA pustulation sub-score increase by ≥ 2 after patients achieved a GPPGA total of 0 or 1. †Patients who received other drugs during week 1 were not eligible to receive OL spesolimab on day 8. GPPGA generalized pustular psoriasis physician global assessment, IV intravenous, OL open-label, SD single dose, SoC standard of care

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End Points

The primary end point was a GPPGA pustulation sub-score of 0 (no visible pustules) at week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at week 1. Further end points included proportion of patients with a GPPGA pustulation sub-score of 0 over time; proportion of patients with a GPPGA total score of 0 or 1 over time; percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) over time; proportion of patients with a GPPASI 75 over time; absolute change from baseline in pain Visual Analog Scale (VAS) score over time; Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score; Psoriasis Symptom Scale (PSS); and dermatology life quality index (DLQI) score.

Adverse events (AEs), including any AEs, investigator-defined drug-related AEs, severe AEs (Rheumatology Common Toxicity Criteria [RCTC] grade 3 or 4), serious AEs (SAEs), AEs leading to discontinuation of spesolimab, as well as the AEs at system organ class (SOC) or preferred term (PT) level that were reported in ≥ 2 patients, were assessed at week 1 through week 12, including the AEs that occurred between the initiation of spesolimab or placebo and the end of the residual-effect period (16 weeks after the last dose of spesolimab) [20].

Statistical Analyses

The primary end point and key secondary end point were analyzed using the Suissa–Shuster Z-pooled test with a type I error of < 0.025 (one-sided). The 95% confidence interval (CI) around the risk difference was generated using the Chan and Zhang method [22]. The primary and key secondary end points were analyzed in a hierarchical manner. When patients used any escape treatment during week 1, or open-label spesolimab on or after day 8, this was considered a non-response in the primary analysis of the primary and key secondary end points. The alternative estimand used non-responder imputation with any value from post death or from any use of escape medication, or open-label spesolimab after day 8.

Further end points included proportion of patients with GPPASI 75, absolute change from baseline in pain VAS score, GPPASI, PSS total score, FACIT–Fatigue total score, and DLQI. Any use of other medications for GPP, or open-label spesolimab after day 8, were considered a non-response in the analysis of further end points.

Mean and standard deviation (SD) were used to describe primary and key secondary end points, as well as GPPASI 75. Median, first quartile (Q1) and third quartile (Q3) were used to describe GPPASI and other patient-reported outcome (PRO) end points. Analyses of all end points were exploratory for the Chinese subgroup. Safety data were summarized in a descriptive manner.

Results

Baseline Demographic and Clinical Characteristics

Of the 16 Chinese patients who were screened in the study, 11 were randomized, with five patients receiving spesolimab and six patients receiving placebo. A total of nine patients completed the planned observation period, among whom one patient in each group prematurely discontinued the trial due to self-withdrawal (shown in Fig. 2). Eight (72.7%) patients were female; three were in the spesolimab group and five in the placebo group. The mean age ± SD of patients was 44.4 ± 10.4 years. Six (54.5%) patients had IL36RN mutation. Nine (81.8%) and two (18.2%) patients, respectively, had a GPPGA total score of 3 (moderate) and 4 (severe). Four (36.4%) and three (27.3%) patients, respectively, had a GPPGA pustulation sub-score of 3 and 4. Median GPPASI total score (range) was 15.2 (7.5–45.0) in the spesolimab group and 24.3 (6.6–39.4) in the placebo group (Table 1).

Fig. 2
figure 2

Patient disposition

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Table 1 Baseline demographic and clinical characteristics
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Escape Treatment and Rescue Treatment

None of the Chinese patients received escape treatment during week 1. Moreover, on day 8, one (20.0%) patient in the spesolimab group and five (83.3%) patients in the placebo group received open-label spesolimab. No patient received rescue treatment with spesolimab after day 8.

Efficacy

Primary End Point and Key Secondary End Point

Overall, 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 at the end of week 1 (risk difference 43.3%; 95% CI –22.6, 86.2). A total of 60.0% and 16.7% of patients in the spesolimab and placebo groups, respectively, achieved a GPPGA total score of 0 or 1 at week 1 (risk difference 43.3%; 95% CI –22.6, 86.2) (Table 2).

Table 2 Proportions of patients with a GPPGA pustulation sub-score of 0, and patients with a GPPGA total score of 0 or 1 at week 1
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Further End Points

The proportion of patients with a GPPGA pustulation sub-score of 0 over time, and the proportion of patients with a GPPGA total score of 0 or 1 over time are presented in Fig. 3. An early separation between the spesolimab and placebo curves during week 1 (i.e., the placebo-controlled period) for both end points showed a rapid response in the spesolimab group. In the placebo group, five (83.3%) patients received open-label spesolimab on day 8. The increase in patient proportions for both end points after week 1 indicated patients’ encouraging responses to spesolimab treatment on day 8 (shown in Supplementary Fig. S1a, b). The treatment effect of spesolimab was generally sustained up to 12 weeks.

Fig. 3
figure 3

Proportion of patients who received spesolimab or placebo on day 1 with a GPPGA pustulation sub-score of 0 (a) and a GPPGA total score of 0 or 1 (b) after day 1 until week 12. Patients who received escape therapy during week 1, or who received open-label spesolimab on or after day 8 were considered non-responders. GPPGA generalized pustular psoriasis global physician assessment

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The percentage change from baseline in GPPASI total score, proportion of patients with a GPPASI 75 over time, and absolute change from baseline in the pain VAS score, FACIT–Fatigue score, PSS score, or DLQI score were also improved in patients treated with spesolimab. The treatment effect of spesolimab on these assessed end points was sustained up to week 12 (shown in Supplementary Fig. S2a–f) [23,24,25,26].

Safety

By week 1, four patients in the spesolimab group and four patients in the placebo group reported at least one AE, while two patients in the spesolimab group and three patients in the placebo group reported investigator-defined drug-related AEs. At the SOC level, two patients (in the spesolimab group) reported infections and infestation events (Table 3). Most of these AEs were mild to moderate in severity and did not lead to drug discontinuation. AEs that were reported in ≥ 2 patients in any treatment group are summarized in Table 3.

Table 3 Overall summary of adverse events at week 1 and up to week 12, including residual-effect period
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At week 12, among patients who received at least one dose of spesolimab, including those who were originally assigned to the placebo group and received open-label spesolimab on day 8, seven patients reported at least one AE and four patients reported investigator-defined drug-related AEs. The number of patients who reported infections and infestations was the same as at week 1 (Table 3).

After day 8, one patient initially assigned to the spesolimab group reported squamous cell carcinoma of skin as an SAE [severe AE (RCTC grade 3)] following open-label spesolimab (i.e., after two doses of spesolimab), which was assessed as not related to the study medication by investigators. This patient had a history of acrodermatitis continua of Hallopeau (ACH) with persistent non-healing pustular lesions that initially covered the entire left hand before treatment, which suggests that the skin carcinoma was likely a progression of the pre-existing ACH lesions.

Discussion

Effisayil 1 is the first randomized, double-blind, placebo-controlled study performed in patients with a GPP flare; it is also the largest study on GPP conducted in a global, ethnically diverse, patient population [21].

In the Chinese patients who participated in the Effisayil 1 trial, a higher proportion of patients receiving spesolimab compared with placebo achieved the primary end point of GPPGA pustulation sub-score of 0, as well as achieved the key secondary end point of GPPGA total score of 0 or 1 at week 1. These results suggest that spesolimab demonstrates efficacy in pustular clearance, with patients achieving clear or almost clear for all skin manifestations. In addition, no death was reported, and the occurrence rates of AEs were comparable between the spesolimab and placebo group with no drug-related SAEs, which suggests an acceptable safety profile of spesolimab. Furthermore, pustule clearance was observed as early as 1 day after treatment (day 2) (shown in Supplementary Fig. S3a, b), which indicates a rapid onset of action with spesolimab. Notable changes from baseline in GPPASI and PROs, including pain VAS scores, PSS, FACIT–Fatigue and DLQI over time in Chinese patients in the spesolimab group further demonstrate the positive treatment effect of spesolimab observed in this study.

The efficacy of spesolimab as reflected by the primary end point and the key secondary end point in Chinese patients at week 1 was consistent with the global study population (GPPGA pustulation sub-score of 0 in the spesolimab and placebo groups: 54.3% versus 5.6%; GPPGA total score of 0 or 1: 42.9% versus 11.1%) [20]. Results for the further end points and PROs in the Chinese patients were also consistent with those from the global study population [20].

Overall, spesolimab showed an acceptable safety profile that was consistent with the global study population. Two patients who received spesolimab reported infections by week 1 and by week 12, respectively, but these were not considered serious, severe, or indicative of opportunistic infections. During week 1, no Chinese patients reported SAEs, compared with 14.3% (5/35) of patients in the spesolimab group and 16.7% (3/18) of patients in the placebo group in the global study population [20]. After day 8, one patient who reported squamous cell carcinoma of skin as an SAE had a history of acrodermatitis continua of Hallopeau (ACH). The skin carcinoma was considered a long-term complication of the ACH lesions and was not considered drug related. Previous studies have reported that squamous cell carcinoma occurred in patients with GPP or acrodermatitis continua and suggested that it was possibly due to chronic inflammation [27,28,29,30,31]. Clinical vigilance is important in patients with GPP presenting nonhealing lesions. The most frequently reported AEs at the SOC level in the Chinese patients by week 1 were skin and subcutaneous tissue disorders, general disorders, and administration site conditions, as well as musculoskeletal and connective tissue disorders in the placebo group, and investigations (including a variety of laboratory measurements) in the spesolimab group. In the global study population, skin disorders, general disorders, infections, and nervous system disorders were the most commonly seen AEs by week 1 [20].

Mutations in IL36RN vary across different ethnicities, and the majority of Chinese patients with GPP who carry mutations have the single-point mutation of IL36RN (c.115 + 6 T > C) (> 90%) [32, 33]. In this study, three (60.0%) and three (50.0%) patients in the spesolimab and placebo groups, respectively, had IL36RN mutations (Table 1); no patients carried the CARD14 or AP1S3 mutations. Previous studies have found that CARD14 variants are predisposing factors for Chinese and Japanese patients with GPP and psoriasis vulgaris [34, 35]. A recent study showed that more patients with homozygous mutation (C/C) of IL36RN have recurrent episodes of GPP, compared with those carrying heterozygous (C/T) mutation of the gene [36]. However, the effect of different IL36RN mutations on GPP manifestations and treatment responses is unknown in the clinic.

The findings of this subgroup analysis explored data for Chinese patients with GPP flares who can potentially benefit from spesolimab, although our results should be interpreted with caution due to the small sample size. However, the findings are encouraging and warrant further investigations on a broader scale. Currently, a 5-year open-label extension study is under investigation to evaluate the long-term efficacy and safety of spesolimab. Another global multicenter, randomized controlled trial, Effisayil 2, which has a larger sample size and longer trial period, is investigating whether spesolimab (subcutaneous dosing regimens) can prevent GPP flares in patients with a history of GPP (NCT04399837).

Conclusion

In the Chinese subpopulation of the Effisayil 1 study, more patients receiving spesolimab had lesion clearance than those with placebo at week 1, demonstrating an acceptable safety profile that was consistent with the global study population.