Commentary: Looking Beyond Plaque Psoriasis: Novel IL-36 Inhibitor for Prevention of Generalized Pustular Psoriasis Flares

Recent decades have seen extraordinary advances and approvals of new therapies for plaque psoriasis, with specific IL-17 and IL-23 inhibitors, biosimilars, and, most recently, novel oral therapies such as TYK-2 inhibitors becoming available.

Nevertheless, patients with other psoriasis subtypes, particularly pustular forms, face more significant treatment challenges, and therapeutic options in these cases remain limited. GPP is a rare and potentially life-threatening condition characterized by the rapid development of sterile pustules on the skin and often accompanied by systemic symptoms. Flares of GPP are unpredictable and have historically necessitated hospitalization for extended periods, with a significant mortality rate of up to 7% during hospitalization or within a year post-discharge.¹

However, recent advancements in GPP treatment include the approval of IL-23 inhibitors in select Asian countries and the development of targeted biologics such as spesolimab and imsidolimab specifically for GPP.² These drugs involve direct inhibition of the IL-36 receptor, which is of particular interest since dysregulation of the IL-36 pathway occurs in many, but not all, GPP cases.^{3, 4}

The EMA and FDA approvals of intravenous spesolimab for GPP flares marked a significant advancement in the treatment landscape for GPP. Clinical trials and emerging research have shown promising results, demonstrating safety and efficacy in managing this challenging condition. However, since few dermatologists provide intravenous infusions in their clinics, this may limit its use in specialized clinics and in-patient settings.

The present study assessed several doses of subcutaneous spesolimab prevention of GPP flares.⁵ Over the course of 48 weeks, significantly fewer patients treated subcutaneously with high-dose spesolimab (600 mg loading dose followed by 300 mg every four weeks) developed GPP flares (n=3 [10%]) compared with the placebo group (n=16 [52%]). The study also noted an absence of flares from week 4 through week 48 in the high-dose group, albeit with a higher incidence of serious adverse events compared to placebo (10% vs. 3%).

This study is valuable considering the underserved GPP patient population. A subcutaneous formulation of spesolimab could offer a more convenient treatment approach, and the study underscores the importance of a proactive treatment approach to prevent flares.

Nonetheless, the balance between treatment efficacy and safety remains crucial, particularly considering the multiple comorbidities seen in GPP patients.¹ Moreover, while promising for GPP, trials have revealed spesolimab’s inefficacy for other psoriasis subtypes, such as palmoplantar pustulosis (PPP), leaving this variant with substantial unmet medical needs.⁶ Thus, while these findings are promising for a subset of psoriasis patients, there is still much to be done for our patients with pustular forms of psoriasis.