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

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Richard Warren
David Burden
Siew Eng Choon
Kenneth Gordon
Lluis Puig
Arash Mostaghimi
Georgios Kokolakis
Na Hu
Patrick Hofmann
Christian Thoma
Milan Anadkat


GPP, spesolimab, Effisayil 2, Subgroups, plaque psoriasis, IL-36 receptor gene mutation


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.


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