New study data on anti-IL-36 therapy

Treatment options for generalized pustular psoriasis have been severely limited. Therefore, there is a high demand for new therapeutic options. Spesolimab is considered a promising hope. In a phase II study, the IL-36 receptor inhibitor excelled with rapid onset and sustained efficacy.

Pustular forms of psoriasis rarely occur. Generalized pustular psoriasis is quite different from the more widespread plaque psoriasis [1]. Characteristic, in addition to erythematous rashes, are the formation of numerous sterile pustules in various localizations [1,2]. In addition, sudden onset of fever, chills, and painful skin lesions may occur with this rare inflammatory skin disease [3–5]. Generalized pustular psoriasis may be associated with life-threatening organ failure and infectious complications. There is a lack of effective treatment strategies to date, and in particular, there is a need for treatment options with a rapid onset of action and long-lasting symptom relief [7].

Spesolimab performed well in Phase II study

Interleukin(IL)-36 plays a central role in the pathogenesis of generalized pustular psoriasis (GPP) [8]. In an open-label phase I study, a single intravenous dose of the anti-IL-36 antibody spesolimab had resulted in rapid healing of pustules in patients with GPP [9]. The effect proved to be independent of mutations in the IL36RN gene. Data from the phase II study were presented at the World Psoriasis & Psoriatic Arthritis Conference 2021 (NCT03782792) [10,11]. In the 12-week, double-blind randomized-controlled trial, 53 patients with an acute episode of GPP were randomized in a 2:1 ratio to the treatment arm (spesolimumab 900 mg, i.v., single dose) and the placebo arm. The primary end point was a GPPGA score of 0 (pustule clearance) at week 1. The main secondary end point was a GPPGA score of 0/1 (complete or near-complete pustule clearance) at week 1.

Excursus: Pilot study on spesolimab in pustular psoriasis palmoplantaris

Based on the efficacy evidence from phase I and phase II trials of spesolimab in generalized pustular psoriasis, researchers suggest that blockade of the IL36 pathway may also be an effective treatment strategy in patients with pustular psoriasis palmoplantaris (PPP) [9,11]. In a recently published phase IIa study, although the primary endpoints were not met, the results, including gene expression analyses, support the notion that upregulation of IL-36 plays a role in the pathogenesis of PPP and may be a relevant therapeutic target [6]. Further investigations are currently underway. In PPP, which is also chronic-recurrent, the formation of sterile pustules in the area of the palms and soles is characteristic.

Primary endpoint and multiple secondary endpoints met

In several efficacy endpoints, treatment with spesolimab (n=35) was shown to be superior to placebo (n=18). A proportion of 54.3% of patients in the spesolimab group versus 5.6% of the placebo group showed a GPPGA* score of 0 at week 1 (p=0.0004). These results persisted throughout the 12-week study period. Regarding the main secondary endpoint, a GPPGA score of 0/1 was documented at week 1 in 42.9% of spesolimab-treated patients, compared to 11.1% on placebo (p=0.012). Other secondary endpoints were also met: 45.7% of patients in the spesolimab arm achieved a 75% improvement in GPPASI** at week 4, compared to 11.1% in the placebo arm (risk difference 34.6 [95% CI, 5.8-55.4], p=0.008). In addition, patients receiving spesolimab treatment reported greater relief of pain symptoms (VAS#) at week 4 in a placebo comparison (p=0.001).

Most adverse events were mild to moderate and similar in both study arms. Non-serious infections occurred more frequently in the spesolimab group than in the placebo group (34.3% vs. 5.6%).

* GPPGA = Generalized Pustular Psoriasis Physician Global Assessment.
** GPPASI = Area and Severity Index for Generalized Pustular Psoriasis.
# VAS = Visual Analog Scale

Conclusion

In summary, IL-36 receptor inhibition with spesolimab in acute relapses of generalized pustular psoriasis showed remarkably rapid symptom reduction in placebo comparisons. Efficacy persisted throughout the 12-week study period and no serious adverse events occurred. Spesolimab is also currently being investigated for efficacy and safety in other indications, including pustular psoriasis palmoplantaris (box) .

Congress: World Psoriasis & Psoriatic Arthritis Conference 2021

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