BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects.
METHODS: In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45 years received a single spesolimab dose by intravenous infusion (IV; 450 mg, 900 mg, or 1200 mg) or subcutaneous (SC) administration (300 mg or 600 mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs).
RESULTS: Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5 years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900 mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved.
CONCLUSIONS: Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects.
BACKGROUND: Clinicaltrials.gov registration: NCT04390568.

暂无摘要。

Generalized pustular psoriasis (GPP) in pregnancy can lead to severe complications for both mother and fetus. The treatment of this disease is challenging, especially in recalcitrant and severe cases. Until present, there are no evidence-based guidelines for the treatment of GPP in pregnancy. Spesolimab, a human monoclonal antibody against the IL-36 receptor, has recently attracted attention as a new therapy for GPP flare. This biologic provides rapid and sustained control of symptoms of GPP flare, although its use in pregnant women has not been reported to date. Here, we report a pregnant woman with refractory GPP who did not respond well to systemic steroids. Administration of spesolimab resulted in complete control of the disease and the birth of a healthy baby. Our case demonstrates that IL-36RN inhibitors are a potentially effective and safe treatment option for GPP in pregnancy.

Generalized pustular psoriasis (GPP) is a rare chronic inflammatory pustular dermatosis that presents as painful erythema with sterile pustules on nonacral skin. No unified standard and guideline for the treatment of GPP has been established. Several biologics have been tried for GPP, with varying success. Acrodermatitis continua of Hallopeau (ACH) is a very rare disabling variant of pustular psoriasis characterized by sterile pustules on the fingers and toes, including the nail bed. Comparatively, treating ACH is highly challenging due to its commonly therapy-resistant disease course. The pathogenic role of IL-36 signaling axis has been currently identified in GPP development. Spesolimab, the first anti-interleukin-36 receptor biologic, has been approved for treating GPP flares and shown promising results. In view of a shared pathogenesis between GPP and ACH, specolimab may be an effective treatment for ACH. Currently, there is no case and clinical trial data exist on this condition. Therefore, this case was aim to describe real-world experience of spesolimab use in ACH coexisting with GPP. We report an Asian patient with a 16-year-history of GPP and ACH with marked pustulosis on the nail bed and onychodystrophy. He received conventional systemic regimen acitretin, cyclosporine and biologics adalimumab and secukinumab, but experienced relapse for skin lesions and refractory for nail lesions. He was then treated with a single dose of spesolimab in combination with secukinumab, which resulted in skin clearance and nearly complete resolution of nail lesions over a 32-week period. Our observation suggests that spesolimab should be considered for the treatment of ACH, especially in the patients with intractable nail lesions and concomitant GPP.

BACKGROUND: Generalized 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.
METHODS: Effisayil 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.
RESULTS: Eleven 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.
CONCLUSIONS: In 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.
BACKGROUND: NCT03782792.

BACKGROUND: We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP).
METHODS: This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician\'s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed.
RESULTS: 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from - 14.6% (95% confidence interval [CI]: - 31.5%, 2.2%) to - 5.3% (95% CI: - 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference - 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo.
CONCLUSIONS: The primary objective to demonstrate a non-flat dose-response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518).
A clinical trial of spesolimab for patients with palmoplantar pustulosis. Palmoplantar pustulosis (PPP) is a painful, difficult-to-treat skin disease that is found on patients’ palms and the soles of their feet. In this clinical trial, we studied an injected medicine called spesolimab for treating patients with PPP. Patients were split into five groups; four groups received different doses of spesolimab and one received placebo (an injection without spesolimab). After 16 weeks, patients receiving placebo switched to spesolimab. We measured the body area affected by PPP and how severe PPP was at week 16. Patients’ doctors also assessed skin affected by PPP. At 16 weeks of treatment, there was no significant difference between spesolimab and placebo in terms of the PPP-affected area and severity. However, more patients had clear or almost clear skin with spesolimab than placebo. Among non-Asian patients, more showed an improvement in their PPP with spesolimab than with placebo; this was not the case with Asian patients. Patients taking spesolimab or placebo reported side effects, of which the most common were colds, aches and headaches. More patients receiving spesolimab reported a reaction at the injection site compared with placebo. We monitored patients for up to 1 year, and results remained similar. We showed that spesolimab may have a modest effect on the body area affected by PPP, as well as the severity of PPP, and did not seem to cause more side effects than placebo, except for reactions at the injection site.

Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare.
To assess the effects of spesolimab over the 12-week study.
The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8.
Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics.
The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab.
Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by flares of widespread erythema with sterile pustules, and can be relapsing with recurrent flares, or persistent with intermittent flares. Spesolimab, a humanized anti-interleukin-36 (IL-36) receptor monoclonal antibody, targets the key IL-36 pathogenetic pathway in GPP. A previous study showed that spesolimab treatment led to rapid pustular and skin clearance in patients with GPP flares, which was sustained for up to 12 weeks. This study investigates the long-term effects of spesolimab on GPP flares, for which no specific treatments are currently available. The Effisayil™ 2 study will assess whether maintenance treatment with subcutaneous spesolimab prevents the occurrence of GPP flares and determine the optimal dosing regimen to achieve this aim.
METHODS: Patients will have a documented history of GPP with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear) at screening and randomization. Patients will be randomized 1:1:1:1 to three groups receiving a 600-mg subcutaneous loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 or 12 weeks, or a 300-mg loading dose followed by a 150-mg maintenance dose administered every 12 weeks, and one group receiving placebo, for 48 weeks. The primary endpoint is time to first GPP flare. If a patient experiences a GPP flare during the randomized maintenance treatment period, an open-label intravenous dose of 900-mg spesolimab will be administered, with an option for a second intravenous dose after 1 week.
CONCLUSIONS: Effisayil™ 2 is the first placebo-controlled study in patients with GPP to investigate whether maintenance treatment with spesolimab can prevent flares and provide sustained disease control. This study will provide valuable insights on the long-term management of patients with this potentially life-threatening skin disease.
BACKGROUND: NCT04399837.
The aim of the Effisayil™ 2 study is to see whether long-term treatment with the antibody spesolimab helps prevent skin flares in people with generalized pustular psoriasis (GPP). Patients can take part in the Effisayil™ 2 study if they have well-controlled GPP before they begin treatment in the study; that is, they will have skin that is clear or almost clear. Patients will be randomly divided into four groups, with similar numbers of patients in each group. In three of the four groups, patients will be given different doses of spesolimab for 48 weeks. In the fourth group, patients will be given a placebo for 48 weeks. The main goal of the study is to see how long it takes patients to have a GPP flare, while they are being given spesolimab or placebo. If any patient has a GPP flare during the study, they can be treated with another dose of spesolimab (and possibly a second dose 1 week later if needed), to help control the GPP flare. In this way, the Effisayil™ 2 study will help doctors and patients to learn how to manage GPP over time, so that GPP flares can be avoided.

Generalized pustular psoriasis is a potentially life-threatening neutrophilic skin disease characterized by recurrent flares of widespread erythema and eruption of sterile pustules. In the Effisayil™ 1 study (NCT03782792), 53 patients with a generalized pustular psoriasis flare were treated with placebo or spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, the first targeted treatment to be studied in a randomized clinical trial. Spesolimab treatment resulted in rapid pustular and skin clearance, with an acceptable safety profile. Here, we evaluate the efficacy and safety of spesolimab in 29 Asian patients in the Effisayil™ 1 study. The primary endpoint, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (no visible pustules) at Week 1, was achieved by 10 patients (62.5%) randomized to spesolimab and one patient (7.7%) randomized to placebo (risk difference 54.8, 95% confidence interval [CI] 17.3-79.8). The key secondary endpoint, a GPPGA total score of 0 or 1 (clear or almost clear skin) at Week 1, was achieved by eight (50.0%) and two (15.4%) patients, respectively (risk difference 34.6, 95% CI -3.1-64.7). This was similar to previously published data in the overall population in whom the primary and key secondary endpoints were achieved by 54% versus 6% and 43% versus 11% of patients, respectively. The percentages of Asian patients randomized to spesolimab with a GPPGA pustulation subscore of 0 and GPPGA total score of 0 or 1 were sustained above 60% for up to 12 weeks. In these patients, patient-reported outcomes also improved and markers of systemic inflammation were normalized. Eleven (68.8%) and eight (61.5%) of spesolimab- and placebo-treated patients, respectively, experienced at least one adverse event. In conclusion, spesolimab improved outcomes in Asian patients compared with placebo, supporting its use in the treatment of generalized pustular psoriasis flares.

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.