First evidence of the efficacy and safety of spesolimab in GPP arose from a proof-of-concept phase I open-label study (NCT02978690) of seven biologic-naive adult patients experiencing a moderate-to-severe GPP flare. The activity of the disease was evaluated using the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score, which has subsequently been validated [17].

At baseline, all patients had an average GPPGA score of 3 (moderate disease). A single intravenous dose of 10 mg/kg of spesolimab was administered at baseline. A GPPGA score of 0 or 1 was achieved in five patients by week 1 and in all patients by week 4, sustained up to week 20. A rapid reduction in C-reactive protein and absolute neutrophil count was also observed. Of note, total clearance of the pustules was seen within 48 h in three patients (47%). Response was obtained regardless of the IL36RN mutation status (present in three of the seven patients). Drug-related adverse effects were mild to moderate in severity and no serious adverse events were reported [17].

The phase II Effisayil clinical trial program assessing spesolimab in GPP consists of three key studies, including Effisayil 1 (NCT03782792), which assessed the efficacy and safety of spesolimab in GPP flares; the phase IIb Effisayil 2 (NCT04399837), which has been conducted to evaluate the effectiveness of the maintenance treatment with spesolimab in preventing recurrence of flares; and the long-term extension of both these trials, Effisayil ON (NCT03886246). The available results to date are summarized in Table 1.

The Effisayil 1 trial was a randomized, placebo-controlled, double-blind, phase II, multicenter study designed to evaluate the efficacy, safety and tolerability of spesolimab in patients with GPP presenting with an acute flare. A total of 53 adults with GPP experiencing an acute flare of moderate-to-severe intensity (required to have a GPPGA score of ≥ 3, new appearance or worsening of existing pustules, a GPPGA pustulation subscore ≥ 2, and a body surface covered with erythema and pustules ≥ 5%, excluding immediately life-threatening flares) were randomly distributed in a 2:1 ratio to receive a single 900 mg intravenous dose of spesolimab (n = 35) or placebo (n = 18) on day 1 [5, 36]. Participants ranged in age from 21 to 69 years (mean 43 years), with female (68%) and Asian (55% vs. 45% Caucasians) predominance [5, 35]. The primary endpoint, defined as the achievement of a GPPGA pustulation subscore of 0 at the end of week 1, was achieved by 19 of the 35 patients (54%) receiving spesolimab versus 1 of 18 (6%) patients receiving placebo (p < 0.001). A GPPGA score of 0 or 1 at week 1, measured as a key secondary endpoint, was reached by 15 of the 35 patients (43%) in the spesolimab group, as compared with 2 of 18 patients (11%) in the placebo group (p = 0.02) [5, 37].

At day 8, patients from both groups were eligible to receive an open-label, single intravenous dose of 900 mg of spesolimab without compromising the initial blinding if they had persistent symptoms (GPPGA ≥ 2 and GPPGA pustulation subscore ≥ 2). Of the 35 patients initially randomized for spesolimab, 34% (n = 12) received a second dose, while 15 of the 18 (83%) patients who were assigned to placebo required the rescue dose. As a result, comparisons between the effect of spesolimab and that of placebo could not be carried out after week 1. Among the 15 patients from the placebo group who later received an open-label spesolimab infusion at week 1, 11 (73%) achieved a GPPGA pustulation subscore of 1 by week 2 (1 week after the infusion) and 8 (53%) reached a GPPGA total score of 0 or 1. After day 8, rescue treatment with a single intravenous dose of 900 mg of spesolimab could be administered in case of reoccurrence of a flare, which occurred in 6 of the 49 patients who completed the 12-week follow-up period [5, 37].

Furthermore, patients treated with spesolimab achieved clinically significant improvements in patient-reported outcomes, such as the pain Visual Analog Scale (VAS), Psoriasis Symptom Score (PSS), and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–Fatigue) scores, as well as the Dermatology Life Quality Index (DLQI). There was a numerical trend for early separation between the spesolimab and placebo groups during the first week, favoring the spesolimab group. Curves began to converge after day 8 and both the spesolimab and placebo groups showed comparable improvements. Sustained response over the 12-week duration of the study was observed in both mentioned clinician- and patient-reported outcomes [5, 37].

Regarding IL36RN mutation status, seven patients (five in the spesolimab group and two in the placebo group) were identified to have IL36RN mutations. Clinical response was obtained regardless of the presence or absence of mutations, although patients with mutations showed faster onset of response [5, 37, 38]. Subanalyses revealed that spesolimab efficacy and safety seem to also be independent of sex, race, body mass index, background medication and clinical characteristics at baseline, such as GPPGA and presence of plaque psoriasis [38].

Effisayil 2 is a multinational, phase IIb, randomized, double-blind, placebo-controlled clinical trial that has been conducted to assess whether maintenance treatment with spesolimab can prevent the occurrence of GPP flares and yield sustained control of the disease, as well as determine the optimal dosing regimen to achieve this aim. A total of 123 patients aged 12–75 years with a documented history of GPP with frequent flares and a GPPGA score of 0 or 1 (clear or almost clear) at baseline were randomized 1:1:1:1 to receive (1) a 600 mg subcutaneous loading dose of spesolimab, followed by a 300 mg maintenance dose every 4 weeks (q4w) [high dose] or (2) every 12 weeks (q12w) [medium dose]; or (3) a 300 mg loading dose followed by a 150 mg maintenance dose q12w (low-dose); or (4) placebo q4w, during a period of 44 weeks with follow-up to week 48. The objectives of the trial included the establishment of dose-response curves and assess whether higher doses of spesolimab demonstrate superiority. The primary endpoint was time to first GPP flare. If a patient experienced a GPP flare during the maintenance treatment period, an open-label intravenous infusion of 900 mg of spesolimab was administered, with an option for a second intravenous dose after 1 week. Secondary outcomes on efficacy included the occurrence of at least one GPP flare by week 48 (key secondary endpoint) and time to worsening (defined as an increase of 4 points from baseline for each score) of the PSS and DLQI up to week 48 [39, 40].

A preponderance of Asian (64%) and female (62%) patients was also documented in this trial and the mean age was 40.4 years. At week 48, 30 of the 31 patients receiving placebo, 27 of 31 patients receiving low-dose spesolimab, 28 of 31 patients receiving medium-dose spesolimab, and 26 of 30 patients receiving high-dose spesolimab completed the trial, with no demonstrated pattern with respect to the reasons for discontinuation between the groups. At week 48, 23% of patients in the low-dose spesolimab group, 29% in the medium-dose group, 10% in the high-dose group, and 52% in the placebo group had at least one GPP flare. The estimated probability of a GPP flare occurring started to diverge between the spesolimab and placebo groups shortly after randomization and remained sustained up to week 48. A non-flat dose-response relationship for spesolimab was shown for the three arms of spesolimab versus placebo on time to first GPP flare, achieving the primary trial objective. No flares were observed after week 4 of spesolimab treatment in the high-dose group, which demonstrated a statistical superiority versus placebo in both primary and key secondary endpoints. On the other hand, lower doses of spesolimab did not achieve statistical significance on the time to GPP flare when compared with placebo [40]. Regarding IL36RN mutation status, among patients with an IL36RN mutation, no patients who received the high-dose spesolimab regimen experienced a flare versus 3 of 4 (75%) patients in the placebo regimen. For patients without an IL36RN mutation, 3 of 19 (16%) patients in the high-dose spesolimab group had a flare, in comparison with 9 of 22 (41%) patients in the placebo group [40].

In numerical terms, spesolimab reduced the risk of PSS and DLQI worsening in the 48-week period compared with placebo, but, with the exception of the reduction in DLQI in the high-dose spesolimab regimen (hazard ratio vs. placebo 0.26, p = 0.001), the threshold of statistical significance was not achieved by the remaining secondary measures [40].

Patients who completed the treatment period were eligible to enter Effisayil ON (NCT03886246), an open-label, 5-year extension trial of spesolimab in GPP [41]. The primary endpoint is to assess the occurrence of treatment-emergent AEs up to week 252 of maintenance treatment with spesolimab. Secondary key endpoints that will be assessed include the recurrence of a flare defined by GPPGA and time required to achieve a GPPGA of 0 or 1 in patients who received a rescue dose of spesolimab for a flare. Additional outcome measures include the change from baseline in PSS and the achievement of a GPPGA pustulation subscore of 0, assessed in each visit throughout the 252 weeks [41].

Phase III, open-label expanded access trials are underway in Japan (NCT05200247) [42] and China (NCT05239039) [43] to provide access to spesolimab to patients experiencing a GPP flare-up who have no alternative treatment options. These trials have already been completed but the results have not yet been published.