Introduction & Objectives: Generalized pustular psoriasis (GPP) is a chronic, rare and potentially life-threatening skin disease, characterized by flares of sterile pustules. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is an effective and approved treatment for GPP flares in adults. Effisayil 2 (NCT04399837) was a pivotal, randomized controlled trial that evaluated the efficacy and safety of subcutaneous spesolimab in preventing GPP flares. Here, we report the effect of high-dose spesolimab versus placebo on GPP lesions. Materials & Methods: Eligible patients with a history of GPP were randomized (1:1:1:1) to receive one of three subcutaneous spesolimab regimens or placebo for 48 weeks. High-dose spesolimab regimen was loading dose 600 mg, followed by maintenance dose 300 mg every 4 weeks. GPP Physician Global Assessment (GPPGA) subscores for erythema, pustules and scaling/crusting, and total score were compared between high-dose spesolimab and placebo groups at baseline and over the treatment period (scale: 0, clear to 4, severe). Results: Proportion of patients with baseline score of 0 for each GPPGA subscore and total score was generally similar between treatment groups, except erythema; (high-dose spesolimab [n=30] vs placebo [n=31]: erythema, 13.3% vs 22.6%; pustules, 66.7% vs 67.7%; scaling/crusting, 23.3% vs 22.6%; total score, 10.0% vs 12.9%). By Week 4, proportion of patients with scores of 0 increased with high-dose spesolimab versus placebo, (erythema, 33.3% vs 19.4%; pustules, 80.0% vs 41.9%; scaling/crusting, 30.0% vs 19.4%; total score, 26.7% vs 16.1%), and high-dose spesolimab group had fewer flares (10.0% vs 35.5%). This trend was maintained at Week 24 (erythema, 36.7% vs 22.6%; pustules, 63.3% vs 45.2%; scaling/crusting, 36.7% vs 19.4%; total score, 33.3% vs 19.4%) and Week 48 (erythema, 36.7% vs 22.6%; pustules, 66.7% vs 45.2%; scaling/crusting, 43.3% vs 25.8%; total score, 36.7% vs 22.6%). There were no new flares after Week 4 in high-dose spesolimab group; however, flares increased with placebo (45.2% at Week 24; 51.6% at Week 48). Conclusion: Versus placebo, high-dose subcutaneous spesolimab resulted in a greater proportion of patients maintaining GPPGA scores of 0, a lower proportion having flares at Week 4, and no new flares after Week 4. This was sustained at Weeks 24 and 48.

Generalized pustular psoriasis (GPP) is a chronic and potentially life-threatening skin disease. In Effisayil 2 (NCT04399837), subcutaneous spesolimab effectively prevented GPP flares. Despite eligible patients requiring clear/almost clear skin at baseline, quality of life (QoL) was still impaired, with an overall mean±standard deviation (SD) Dermatology Life Quality Index (DLQI) total score of 8.1±6.4, demonstrating the chronic nature of GPP. We assessed baseline DLQI scores to understand what aspects of patients' lives were impacted by GPP. Patients evaluated 10 questions across six domains on a 0–3 scale; combined scores gave the total DLQI score (0–30), with higher scores indicating greater impact. Mean±SD baseline total DLQI score was 3.7±5.2 versus 8.8±6.3 for patients with a GPP Physician Global Assessment score of 0 (n=16) or 1 (n=105), respectively. Mean±SD baseline total DLQI scores were similar between patients who were or were not treated with systemic GPP medication at randomization (8.1±6.5 vs 8.1±6.1). Patients reported that GPP most affected QoL based on DLQI questions 1, 2, and 4, with mean±SD scores of 1.1±0.8, 1.0±0.8, and 1.0±0.9, respectively; therefore, itch, pain, embarrassment, and the effect of GPP on their choice of clothing had the biggest impact on QoL versus other factors. Baseline DLQI scores in Effisayil 2 highlight the severe impact of GPP on patients' QoL between flares, with the greatest impact observed on itch, pain, feelings of embarrassment, and choice of clothing. Our findings indicate an urgent need for targeted treatments that maintain clearance of chronic skin symptoms.

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Intravenous spesolimab, an anti-interleukin-36 receptor antibody, is approved for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well-tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Introduction Generalized pustular psoriasis (GPP) is a chronic and potentially life-threatening disease characterized by flares of widespread skin pustulation. In Effisayil 2 (NCT04399837), high‑dose spesolimab was superior to placebo in GPP flare prevention and numerically reduced the risk of Dermatology Life Quality Index (DLQI) worsening (≥4-point increase in total score from baseline; secondary endpoint), up to Week 48. Methods Here, we further analyze the effect of high-dose spesolimab versus placebo on DLQI in Effisayil 2. Results Baseline characteristics were generally similar in the high-dose spesolimab (600 mg loading dose then 300 mg every 4 weeks [N=30]) and placebo groups (N=31) in terms of sex, age, length of disease, and historical flare frequency, although the high‑dose spesolimab group had a higher mean±SD DLQI score (11.1±6.9 [missing=1]) versus placebo (7.2±5.6 [missing=0]). At Week 4 in exploratory analysis, more patients in the high-dose spesolimab group (N=29) had no GPP flare and ≥4-point improvement in their DLQI score versus placebo (N=31) (n/N [%]: 10/29 [34.5%] [missing=1] versus 3/31 [9.7%] [missing=0]) at Week 4; this was also seen at Week 48 (11/29 [37.9%] [missing=6] versus 8/31 [25.8%] [missing=0], respectively). Furthermore, a higher proportion of patients treated with spesolimab had no GPP flare and reached a DLQI score of 0 or 1 at all visits up to Week 48 versus placebo (7/29 [24.1%] versus 1/31 [3.2%], respectively). Conclusion Adding to previous data from Effisayil 2, this analysis demonstrates that patients treated with spesolimab (including high-dose) rapidly gained improvements in DLQI scores versus placebo, which were sustained through to Week 48.

Generalized pustular psoriasis (GPP) is a chronic and potentially life-threatening disease characterized by flares of widespread skin pustulation. In Effisayil 2 (NCT04399837), high-dose spesolimab was superior to placebo in GPP flare prevention and numerically reduced the risk of Dermatology Life Quality Index (DLQI) worsening (≥4-point increase in total score from baseline; secondary endpoint), up to Week 48. Here, we further analyze the effect of high-dose spesolimab versus placebo on DLQI in Effisayil 2. Baseline characteristics were generally similar in the high-dose spesolimab (600 mg loading dose then 300 mg every 4 weeks [N=30]) and placebo groups (N=31) in terms of sex, age, length of disease, and historical flare frequency, although the high-dose spesolimab group had a higher mean±SD DLQI score (11.1±6.9 [missing=1]) versus placebo (7.2±5.6 [missing=0]). At Week 4 in exploratory analysis, more patients in the high-dose spesolimab group (N=29) had no GPP flare and ≥4-point improvement in their DLQI score versus placebo (N=31) (n/N [%]: 10/29 [34.5%] [missing=1] versus 3/31 [9.7%] [missing=0]) at Week 4; this was also seen at Week 48 (11/29 [37.9%] [missing=6] versus 8/31 [25.8%] [missing=0], respectively). Furthermore, a higher proportion of patients treated with spesolimab had no GPP flare and reached a DLQI score of 0 or 1 at all visits up to Week 48 versus placebo (7/29 [24.1%] versus 1/31 [3.2%], respectively). Adding to previous data from Effisayil 2, this analysis demonstrates that patients treated with spesolimab (including high-dose) rapidly gained improvements in DLQI scores versus placebo, which were sustained through to Week 48.

Introduction: Generalized pustular psoriasis (GPP) is characterized by flares of widespread pustulation and erythema that may be fatal. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved to treat GPP flares. Effisayil 2 trial (NCT04399837) assessed efficacy and safety of spesolimab for prevention of GPP flares over 48 weeks. Here we show the efficacy of high-dose subcutaneous (SC) spesolimab for GPP flare prevention in prespecified subgroups in Effisayil 2. Methods: Eligible patients were randomized 1:1:1:1 to receive placebo, or low- (300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (600 mg LD; 300 mg q12w) or high-dose (600 mg LD; 300 mg every 4 weeks) SC spesolimab over 48 weeks. We assessed the efficacy of high-dose spesolimab versus placebo across prespecified subgroups (including IL36RN mutation, comorbid plaque psoriasis [PsV], and body mass index [BMI] status) for the primary endpoint, time to first GPP flare by Week 48 (defined as a ≥2 GPPGA total score increase from baseline and ≥2 GPPGA pustulation score increase from baseline; subsequent use of rescue SC spesolimab also indicated a GPP flare), using a Cox regression analysis stratified by systemic use of GPP medications at randomization. Key secondary endpoint was proportion of patients with ≥1 GPP flare by Week 48. Results: 123 patients were randomized (placebo, N=31; high-dose spesolimab, N=30). Hazard ratios (95% CI) for the primary endpoint favored high-dose spesolimab vs placebo in most prespecified subgroups, including: with IL36RN mutation, 0.04 (0.002, 1.152); without IL36RN mutation, 0.41 (0.109, 1.537); PsV absent at baseline, 0.14 (0.031, 0.629); PsV present at baseline, 0.22 (0.025, 1.883); and BMI <25 kg/m2, 0.22 (0.057, 0.816); 25 to <30 kg/m2, 0.12 (0.005, 2.817); and ≥30 kg/m2, 0.23 (0.008, 6.033). For the key secondary endpoint, adjusted risk differences (95% CI) by Week 48 were lower in those receiving high-dose spesolimab vs placebo in these prespecified subgroups: with IL36RN mutation, -0.75 (-1.000, -0.326); without IL36RN mutation, -0.22 (-0.504, 0.074); PsV absent at baseline, -0.41 (-0.672, -0.154); PsV present at baseline, -0.32 (-0.830, 0.191); and across all BMI subgroups. Conclusion: Over 48 weeks, high-dose spesolimab was effective at preventing GPP flares irrespective of IL36RN mutation, comorbid PsV and BMI status at baseline.

Introduction: Generalized pustular psoriasis (GPP) is a chronic, rare disease characterized by flares of widespread skin pustulation. Intravenous (IV) spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved for GPP flare treatment; however, the optimal dosing and long-term efficacy of subcutaneous (SC) spesolimab treatment in patients with GPP has not yet been reported. We report the effect of SC spesolimab on achieving sustained disease remission in Effisayil 2 (NCT04399837), a 48-week trial that evaluated the efficacy and safety of SC spesolimab in preventing GPP flares. Methods: Patients with a history of GPP were randomized (1:1:1:1) to receive placebo (n=31), low- (n=31, 300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (n=31, 600 mg LD; 300 mg q12w) or high-dose (n=30, 600 mg LD; 300 mg every 4 weeks [q4w]) SC spesolimab over 48 weeks. Sustained remission was defined as GPP Physician Global Assessment (GPPGA) total score of 0 or 1 at all visits up to Week 48, or GPPGA total score of 0 or 1 and all GPPGA subscores ≤2 at all visits up to Week 48. Sustained pustular clearance was defined as GPPGA pustulation subscore of 0 at all visits from Week 4 to Week 48. Any use of IV spesolimab or another standard of care for GPP worsening was considered a failure of remission. Missing data were imputed by a sequential logistic regression multiple imputation method. Adjusted risk differences (RD) were calculated by the Mantel−Haenszel type-weighted average of differences. Results: 31 patients received placebo, and 30 patients received high-dose spesolimab. Compared to placebo, more patients had sustained remission in the high-dose arm using both GPPGA total score 0 or 1 (63.3% vs 29.0%; RD [95% CI] 0.35 [0.10–0.59]), and GPPGA total score 0 or 1 and all GPPGA subscores ≤2 (60.4% vs 29.0%; RD [95% CI] 0.32 [0.07–0.56]). Compared to placebo, more patients in the high-dose arm had sustained pustular clearance over 48 weeks (63.6% vs 25.8%; RD [95% CI] 0.38 [0.14–0.62]). Conclusion: Overall, high-dose SC spesolimab q4w is effective for the long-term management of GPP skin symptoms.