# New and Emerging Treatments for Generalized Pustular Psoriasis: Focus on IL-36 Receptor Inhibitors
## 5 New Treatments for GPP
### Spesolimab  
Spesolimab is the first agent developed to target the IL-36 proinflammatory pathway. It consists of a humanized monoclonal immunoglobulin G1 antibody that targets the IL-36R. By binding to this receptor, spesolimab blocks it, preventing the IL-36 ligands from activating it and thereby inhibiting the inflammatory response [36; 37]. Currently, spesolimab has been approved by the FDA, EMA, and Japan for the treatment of GPP flares. In addition to GPP, it is also being studied for use in other autoimmune conditions, such as ulcerative colitis, [PERSON]'s disease, palmoplantar pustulosis, and hidradenitis suppurativa [37]. Spesolimab's safety and efficacy were first evaluated in a phase I clinical trial involving seven patients with an ongoing GPP flare, who were given a single IV dose of spesolimab (Table 1). Initially, all patients had a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 3 (moderate disease) By Week 1, five of the patients had already reached a score of 0 or 1 (clear or almost clear skin). By Week 4, all of them had achieved the same results and maintained them until the 20 th week. None of the adverse effects were considered serious [38; 39]. Effisayil 1, a phase II, multicenter, randomized, double-blind, placebo-controlled clinical trial, involved 53 patients with a GPP flare (Table 1). The patients were randomly assigned in a 2:1 ratio to either the spesolimab group, receiving a single 900 mg IV dose of spesolimab, or the placebo group. After Week 1, patients in both groups had the option to receive a dose of spesolimab on Day 8 as rescue medication, or both [40]. To assess spesolimab's efficacy in the treatment of GPP, the investigators proposed evaluating the patients' GPPGA constellation subscore and GPPGA total score. The primary outcome was a GPPGA constellation subscore of 0 at Week 1, and the key secondary outcome was a GPPGA total score of 0 or 1 at Week 1. Both scores range from 0 to 4, with higher scores indicating more severe disease [40]. At the beginning of the trial, all the patients had a GPPGA constellation subscore of at least 2 and a GPPGA total score of at least 3 (moderate-to-severe intensity). By the end of Week 1, 54% of the patients in the spesolimab group had a GPPGA constellation subscore of 0, and 43% had a GPPGA total score of 0 or 1 This response was significantly higher compared to the placebo group, where only 6% achieved a GPPGA constellation subscore of 0 and 11% achieved a GPPGA total score of 0 or 1 [40]. On Day 8, 83% of the placebo-randomized patients received a rescue dose of spesolimab, while only 34% of the patients who had already been administered spesolimab needed a second dose This made it impossible to further compare the effects of spesolimab and the placebo. Among the placebo-assigned patients who received a spesolimab rescue dose on Day 8, 73% had reached a GPPGA constellation subscore of 1 by Week 2, and 53% had reached a GPPGA total score of 0 or 1 [39; 40]. Very recently, Effisayil 2, another multicenter, randomized, placebo-controlled, phase 2b trial involving 123 patients with a history of frequent flares and a GPPGA score of 0 or 1