Fighting the Flare of GPP: Expert Insights on Spesolimab

Generalized pustular psoriasis (GPP) is a rare yet severe condition characterized by recurrent flares, leading to substantial physical and emotional distress for patients. In a Dermatology Times Between the Lines custom video series, Bruce Strober, MD, PhD, a clinical professor of dermatology at Yale University, and Aaron Farberg, MD, chief medical officer at Bare Dermatology, explored a pivotal study on spesolimab-sbzo (Spevigo; Boehringer Ingelheim), a medication designed to prevent GPP flares.

The Burden of GPP Flares

GPP is not merely a skin condition; it is “one of the few medical emergencies that we have in dermatology,” according to Farberg. Patients often experience profound anxiety about impending flares, which can lead to systemic symptoms and potentially fatal outcomes. He described the psychological toll of GPP: “It’s a traumatic, dramatic experience.… It could be a very impactful flare, which is very scary and worrisome for these patients.”

In addition to physical symptoms such as pain and malaise, GPP flares severely impact quality of life. Patients often feel constitutionally unwell, leading to a state of helplessness as they confront the unpredictability of their condition.

Challenges in Management

Farberg emphasized the difficulties in managing GPP, particularly due to its unpredictable nature and lack of reliable biomarkers to predict flares. “It would be great if there was some sort of indicator or a lab or a biomarker that we could utilize to know when there could potentially be a flare,” he noted. Current treatment strategies often rely on trial and error, with dermatologists frequently prescribing various biologics, but these approaches have been largely ine ective in preventing flares.

Farberg likened the treatment landscape for GPP prior to the introduction of spesolimab to the “Wild West,” with dermatologists struggling to find effective therapies. “We were trying and using all sorts of different treatments,” he explained, indicating a desperate need for targeted therapies.

Introduction to Spesolimab

Initially available in an intravenous (IV) formulation for acute flares, this study explored a subcutaneous formulation designed for flare prevention. The rapid efficacy of spesolimab in treating acute flares is well documented, with most patients experiencing resolution of pustulation within 7 days of treatment.

The recent study aimed to evaluate the effectiveness of this formulation in preventing GPP flares over an extended period. “This is a groundbreaking study…the impact it’s going to have on our patients,” Farberg noted.

Study Design and Methodology

The study involved a large multinational clinical trial focused on patients aged 12 to 75 years with a history of GPP. Key eligibility criteria included the following:

• A documented history of at least 2 past GPP flares.
• A Physician Global Assessment score of 0 or 1 at screening, indicating minimal disease activity at enrollment.
• A washing out from any prior GPP treatments before randomization.

The dosing regimens included various loading and maintenance doses of spesolimab, with some patients receiving a placebo. Notably, patients experiencing a flare during the trial were given an IV dose of spesolimab.

End Points and Outcomes

The primary end point was the time to the first GPP flare within 48 weeks, while secondary end points assessed the occurrence of at least 1 flare by week 48 and the comparative efficacy of different dosing regimens vs placebo. Reflecting on the study’s strengths, Farberg highlighted its well-designed nature, which avoided post hoc analyses. He noted that the primary end point was straightforward: “How soon were you going to flare?”

Strengths and Limitations of the Study

While the study has significant strengths, such as its ethical design and real-world applicability, there were some limitations. The sample size, while substantial for such a rare disease, could still be larger for more robust data. Farberg pointed out, “The only weakness there was that we would all love to see a greater sample size.”

Another potential limitation was the variability in the management of patients who experienced a flare. Each investigator had discretion regarding whether patients could switch back to a monthly dosing regimen after experiencing a flare, introducing a degree of subjectivity into the results.

Safety Profile and Adverse Events

Safety was a critical topic in the discussion. Farberg noted that the adverse event profile associated with spesolimab was largely reassuring, with no new safety concerns identified when compared with placebo. He stated, “There otherwise were no hypersensitivity reactions and nothing else to really point out,” although he acknowledged a slight increase in infections and injection site reactions, which are typical in such patient populations.

Strober emphasized the need for caution in interpreting safety data from small study populations. While he acknowledged the lack of dosedependent adverse events as a positive indicator, he underscored the importance of continuous monitoring for infections, especially considering the severe nature of GPP.

Clinical Implications of Treatment

The discussion also touched on the occurrence of pustular psoriasis as an adverse event in some patients. Farberg suggested this might represent a manifestation of the disease rather than a direct consequence of treatment, indicating the need for ongoing evaluation of patient responses to spesolimab. He acknowledged the complexities of treating GPP, especially in patients with comorbid conditions.

Strober noted that understanding the natural history of GPP and conducting postapproval safety analyses will be essential for interpreting these findings in real-world settings.