Rapid pustule and skin clearance with IL-36 receptor inhibitor spesolimab

The first randomised, placebo-controlled trial in patients with generalised pustular psoriasis (GPP) demonstrated that IL-36 receptor inhibition with spesolimab resulted in rapid improvements in signs and symptoms of flares versus placebo, with sustained effects and a favourable benefit-risk profile [1].

GPP is a rare, potentially life-threatening, multisystemic autoinflammatory disease characterised by widespread recurrent flares of sterile pustules on the skin. Dysregulation of the IL-36 pathway appears to be central in its pathogenesis [2]. Currently, no therapies have been approved for flares of GPP in the USA or Europe.

In a previous phase 1 study (NCT02978690), a single intravenous dose of spesolimab resulted in rapid pustule clearance in patients with GPP [3]. The subsequent phase 2 Effisayil 1 study (NCT03782792) was a 12-week, double-blind, randomised, placebo-controlled trial including 53 patients with a flare of GPP that evaluated the efficacy and safety of spesolimab. The results were shared by Prof. Hervé Bachelez (Hôpital Saint-Louis, France).

A GPP Physician Global Assessment (GPPGA) pustulation subscore of 0 (i.e. pustule clearance) at week 1 was achieved by 54.3% of patients receiving spesolimab versus 5.6% receiving placebo (one-sided P=0.0004; see Figure) [1]. These results were sustained throughout the 12-week study. A GPPGA score of 0/1 (clear/almost clear) at week 1 was achieved by 42.9% of patients receiving spesolimab versus 11.1% receiving placebo (one-sided P=0.012).

Figure: GPPGA pustulation subscore of 0 at week 1 [1]



CI, confidence interval; GPPGA, generalised pustular psoriasis Physician Global Assessment.

At week 4, 45.7% of patients receiving spesolimab achieved a 75% improvement in GPP Area and Severity Index (GPPASI) versus 11.1% receiving placebo (risk difference 34.6; one-sided P=0.008). In addition, patients receiving spesolimab reported greater reductions in pain visual analogue scale (VAS; P=0.001) at week 4 versus patients receiving placebo.

The overall safety profile of spesolimab was acceptable. Most adverse events were mild to moderate and similar between both study arms. Non-serious infections rates were higher in the spesolimab group (34.3%) compared with the placebo group (5.6%), with no patterns in pathogen or affected organs.

Spesolimab treatment of flares of GPP was associated with rapid pustule and skin clearance within 1 week and was sustained through 12 weeks. These findings support spesolimab as a potential therapeutic option for patients with GPP flares. Long-term administration of spesolimab is being evaluated as a subcutaneous formulation in an ongoing 5-year, open-label extension study in the Effisayil 2 study (NCT04399837).

1. Bachelez H, et al. Effisayil 1: A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of spesolimab in patients with a generalized pustular psoriasis flare. Abstract O3, 6^thWorld Psoriasis & Psoriatic Arthritis Conference, 30 June–3 July 2021.
2. Gooderham MJ, et al. Expert Rev Clin Immunol. 2019;15:907–19.
3. Bachelez H, et al. N Engl J Med. 2019;380:981–3.

 

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Posted on 17 September 202129 February 2024