Treatment with IV spesolimab led to a higher incidence of lesion clearance at one week in patients with generalized pustular psoriasis (GPP), according to results from a phase II trial.
In the placebo-controlled study, 54% of the patients who got the interleukin-36 (IL-36) receptor inhibitor had a pustulation subscore of 0 (down from baseline subscores of 3 or 4) at the end of week one versus 6% in the placebo group, for a difference of 49 percentage points (95% CI 21-67, P<0.001), reported Mark G. Lebwohl, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and co-authors in the Effisayil 1 Trial group.
Patients on the study drug also saw improvements for the primary endpoint, Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) subscores, they stated in the New England Journal of Medicine.
However, among patients who received spesolimab at any time in the trial, infections occurred in 47% at week 12, while antidrug antibodies were detected in 46% of patients who got at least one dose of spesolimab, the authors noted, although they added that there was “no particular pathogen or affected organ.”
They called for “[l]onger and larger trials… to determine the effect and safety of spesolimab in patients with pustular psoriasis.”
The findings shine an even brighter spotlight on spesolimab, which has been having a moment in the past few months. In the October Journal of Allergy and Clinical Immunology, an open-label, proof-of-concept trial demonstrated that spesolimab downregulated IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation as early as week one in patients with GPP, according to Patrick Baum, PhD, of Boehringer Ingelheim in Biberach an der Ris, Germany, and co-authors.
Also in October, the European Medicines Agency validated developer Boehringer Ingelheim’s marketing authorization application (MAA) and put it under evaluation for the treatment of GPP flares. In December, the FDA gave the agent priority review in the same indication, and also granted it Orphan Drug and Breakthrough Therapy Designations, according to the company.
“Generalized pustular psoriasis is becoming of greater interest because there are drugs recently approved for use in Asian countries, such as interleukin (IL)-23 inhibitors, as well as biologics, imsidolimab and spesolimab, being specifically developed for generalized pustular psoriasis. They particularly involve direct inhibition of the IL-36 receptor (IL-36R),” explained Bruce Strober, MD, PhD, of Central Connecticut Dermatology/Yale School of Medicine in Cromwell, and New Haven, Connecticut, respectively, in an interview with Dermatology Times.
Strober was the project chair for the International Psoriasis Council (IPC), which in 2020 produced a “Delphi consensus” for the recategorization of psoriasis. In brief, the consensus states that “Psoriasis patients should be classified as either candidates for topical therapy or candidates for systemic therapy; the latter are patients who meet at least one of the following criteria: (1) body surface area >10%, (2) disease involving special areas, and (3) failure of topical therapy.”
In a 2021 online IPC talk, Francesca Capon, PhD, of King’s College London, explained that, based on genetic etiology, GPP is caused by abnormal IL-36 signaling, and that recessive IL36RN mutations are found in about a quarter of GPP cases. Capon’s group also “identified a further gene, AP1S3, as associated with GPP, and what we found is that AP1S3 mutation could also upregulate IL-36 signaling through different mechanisms… that really showed us that GPP is a disease of excessive IL-36 activation.” Capon also pointed out that the effects of IL-36 “in the skin and in circulation are important because… IL-36 is now a well-established therapeutic target,” citing a successful 2019 phase II trial of spesolimab.
German researchers tested spesolimab in a phase IIa trial in patients with palmoplantar pustulosis (PPP), and reported that PPP severity declined over time faster in the spesolimab arm versus placebo, but the study was limited by a small sample size (n=40) and lower overall disease severity.
The current trial randomly assigned 35 patients (60% female; 46% Asian) with GPP to spesolimab, at a single 900-mg IV dose, and 18 GPP patients to placebo (83% female; 72% Asian). With regard to the predominantly Asian patient population, Lebwohl’s group explained that GPP is a rare disorder and its estimates of prevalence suggest that the condition is about five times more common in Asia than in Europe and the U.S. They acknowledged that the small patient population was a study limitation.
“Patients in both groups could receive an open-label dose of spesolimab on day eight, an open-label dose of spesolimab as a rescue medication after day eight, or both and were followed to week 12,” they explained. About one-third of the patients in the treatment arm received open-label spesolimab as did 15 of the 18 in the placebo arm after the one-week randomized period.
The primary endpoint of the trial was a pustulation subscore of 0 (no visible pustules) at the end of week one, according to GPPGA (range 0 to 4=severe pustulation). The secondary endpoint was a GPPGA score of 0 to 1 at the end of week one.
The investigators reported that 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3 at baseline, the remaining 37% and 33% of patients, respectively, had a pustulation subscore of 4.
Also, 43% in the study-drug arm had a GPPGA score of 0 to 1 versus 11% in the placebo arm for a 32-percentage point difference between the two arms (95% CI 2-53, P=0.02).
As for infections, 17% in the spesolimab arm experienced them through the first week, with three cases each of urinary tract infection and influenza. For adverse events (AEs), at week 12, 82% of the patients who received at least one dose of spesolimab—including those assigned to placebo who then got open-label spesolimab at day eight—had an AE, and 12% had serious AEs, such as drug reaction with eosinophilia and systemic symptoms, the authors reported.
Lebwohl’s group noted that long-term spesolimab administration with a subcutaneous formulation is under evaluation in the Effisayil 2 trial (estimated study completion date 2023).
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In patients with generalized pustular psoriasis, the investigational interleukin-36 receptor inhibitor spesolimab offered higher incidence of lesion clearance at one week versus placebo in a phase II trial.
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Intravenous treatment with spesolimab was associated with infections and systemic drug reactions.
Shalmali Pal, Contributing Writer, BreakingMED™
Effisayil 1 is supported by Boehringer Ingelheim. Some co-authors are company employees.
Lebwohl and co-authors reported multiple relationships with, and/or support from, multiple entities including Boehringer Ingelheim.
Cat ID: 10
Topic ID: 75,10,730,10,105,192,919,925
