Effect of Subcutaneous Spesolimab on the Prevention of Generalized Pustular Psoriasis Flares Over 48 weeks: Subgroup Analyses from the Effisayil 2 Trial

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.