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Patients with severe generalized pustular psoriasis (GPP) had rapid clearance of skin lesions when treated with an investigational interleukin (IL)-36 inhibitor, a small randomized trial showed.

One week after treatment with intravenous spesolimab, more than half of patients with GPP had complete clearance of skin pustules. In contrast, only 6% of placebo-treated patients met clinical criteria for clearance. Significantly more patients in the spesolimab group had global improvement in GPP at 1 week.

Drug reactions occurred in two patients treated with spesolimab, and infections were common in patients treated with the monoclonal antibody, including patients who crossed over from placebo to spesolimab, reported Mark Lebwohl, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and co-authors in the .

"The results of the current trial with a single infusion of spesolimab add to findings from a previous open-label study of spesolimab and support the hypothesis that interleukin-36 is involved in the pathogenesis of GPP," the authors concluded. "Long-term administration of spesolimab is being evaluated with a subcutaneous formulation in the five-year open-label trial ... and the on prevention of flares."

"In this phase II trial involving patients with flares of GPP, intravenous spesolimab resulted in higher rates of clearance of pustular lesions at one week than placebo but was associated with infections and systemic reactions. Longer and larger trials are warranted to determine the effect and safety of spesolimab in patients with pustular psoriasis."

The study results "are truly remarkable" and suggest spesolimab could have a major impact on patients with GPP, according to Joel Gelfand, MD, of the University of Pennsylvania in Philadelphia.

"GPP is a very rare but devastating, life-threatening disease that presents with the sudden onset of pustules throughout the skin," Gelfand told MedPage Today via email. "Patients can have fever and joint pains and often need to be hospitalized. Without rapid treatment it can result in death. Currently there are no FDA approved treatments for this orphan disease."

"GPP is an orphan disease that requires rapid and effective treatment in order to avoid poor outcomes such as hospitalization and death," he added. "Spesolimab offers a tremendous step forward for our patients. Longer term studies with a comparator, such as a biologic that targets IL-17, would be helpful to more fully understand the safety, efficacy, and role spesolimab will have in real world patients."

An autoinflammatory skin disease, GPP causes widespread eruption of sterile pustules that may be accompanied by systemic symptoms and extracutaneous manifestations, such as arthritis and neutrophilic cholangitis, the authors noted. GPP can have a relapsing clinical course associated with recurrent flares or persistent with intermittent flares. Mortality estimates range from 2% to 16%, attributable to sepsis and cardiorespiratory failure.

Drugs that target tumor necrosis factor-alpha, interleukin (IL)-17, IL-17 receptor, and IL-23 have approved indications for GPP outside the U.S., but the approvals are based on limited clinical data, mostly from trials of plaque psoriasis and small, nonrandomized studies of GPP, the authors continued. Interest in IL-36 as a potential therapeutic target originated with observations of loss-of-function mutations in the IL-36 receptor antagonist gene and related genes and overexpression of IL-36 in GPP skin lesions.

In a small phase I study, a single dose of the humanized anti-IL-36 receptor antibody spesolimab produced clinical improvement in patients with GPP flare. The results led to the phase II randomized trial in patients with GPP flare.

Investigators randomized 53 patients 2:1 to a single intravenous dose of spesolimab or placebo. The primary endpoint was the GPP Physician Global Assessment pustulation subscore (0=no visible pustules, 4=severe pustulation) at the end of 1 week, and follow-up continued to week 12. An early response assessment was chosen because of the life-threatening potential of acute and severe flares of GPP, the authors noted.

The study population had a median age of 43, mostly women (67%), and baseline pustulation subscore of 3 in 43% of the patients and 4 in 36%. On day 8, 18 of 35 (54%) patients in the spesolimab arm had a GPP pustulation subscale score of 0 as compared with one of 18 (6%) in the placebo group (P<0.001). Additionally, 15 of 35 patients in the spesolimab arm had a total global assessment score of 0 or 1 (nearly clear) as compared with two of 18 (11%) in the placebo group (P=0.02).

During the first week, two patients in the spesolimab arm had drug reactions -- one associated with eosinophilia and systemic symptoms and one with drug-related hepatic injury. Six patients in the spesolimab group and one in the placebo group developed infections. By week 12, 47% of patients had developed infections, including patients who crossed over to spesolimab from the placebo group.

Serious adverse events occurred in two spesolimab-treated patients during the first week and two others by week 12 versus none in the placebo group.

Laboratory studies revealed anti-drug antibodies in 46% of patients who received at least one dose of spesolimab, including those who crossed over from the placebo group.

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