• Hervé Bachelez, Siew-Eng Choon, Slaheddine Marrakchi, A David Burden, Tsen-Fang Tsai, Akimichi Morita, Alexander A Navarini, Min Zheng, Jinhua Xu, Hamida Turki, Milan J Anadkat, Sushmita Rajeswari, Hairui Hua, Sebastian D Vulcu, David Hall, Kay Tetzlaff, Christian Thoma, Mark G Lebwohl, and Effisayil 1 Trial Investigators.
• From Service de Dermatologie, Assistance Publique-Hôpitaux de Paris Hôpital Saint-Louis, and INSERM Unité 1163, Imagine Institute of Genetic Diseases, Université de Paris - both in Paris (H.B.); the Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Clinical School Johor Bahru, Monash University Malaysia, Subang Jaya, Malaysia (S.-E.C.); the Dermatology Department, Hedi Chaker University Hospital, Sfax, Tunisia (S.M., H.T.); the Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom (A.D.B.); the Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (T.-F.T.); the Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan (A.M.); the Department of Dermatology, University Hospital Basel, Basel, Switzerland (A.A.N.); the Department of Dermatology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou (M.Z.), and the Department of Dermatology, Huashan Hospital, Fudan University (J.X.), and Boehringer Ingelheim (China) Investment Company (H.H.), Shanghai - all in China; Washington University School of Medicine, Division of Dermatology, St. Louis (M.J.A.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (S.R., D.H.); Boehringer Ingelheim International, Ingelheim (S.D.V., K.T.), the Medical Clinic, Department of Sports Medicine, University of Tuebingen, Tuebingen (K.T.), and Boehringer Ingelheim International, Biberach (C.T.) - all in Germany; and the Icahn School of Medicine at Mount Sinai, New York (M.G.L.).
• N. Engl. J. Med. 2021 Dec 23; 385 (26): 2431-2440.

BackgroundGeneralized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.MethodsIn a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.ResultsA total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.ConclusionsIn a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).Copyright © 2021 Massachusetts Medical Society.

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