Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study

Abstract

Introduction We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). Methods This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician’s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. Results 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from − 14.6% (95% confidence interval [CI]: − 31.5%, 2.2%) to − 5.3% (95% CI: − 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference − 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. Conclusion The primary objective to demonstrate a non-flat dose–response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518). Supplementary Information The online version contains supplementary material available at 10.1007/s13555-023-01002-1.

Spesolimab: Is it a new treatment target in palmoplantar pustulosis?

“…In addition, efficacy variations in ethnicity and severity of disease were observed in the clinical studies described above 9,10 . It is an interesting point that the efficacy was more pronounced in non‐Asian patients.…”

“…Spesolimab is a humanized anti‐interleukin‐36 receptor monoclonal antibody, showing a great lesion clearance incidence in patients with generalized pustular psoriasis (GPP) 8 . However, neither of the two published clinical trials of spesolimab for PPP met the primary efficacy endpoint, which indicated its modest benefits in palmoplantar pustulosis 9,10 . Although GPP and PPP are considered two major subtypes of pustular psoriasis, they have many differences.…”

Response to: Letter to Editor Regarding “Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study”

“…We thank Dr Hu and colleagues for their Letter to the Editor regarding our Phase IIb study of spesolimab in palmoplantar pustulosis (PPP) [ 1 ], and we welcome this opportunity to discuss the important points raised. The refractory nature of PPP means that there are limited treatment options for patients [ 2 ], and any factors potentially influencing treatment response should be explored to enable future clinical trial planning.…”

“… First, Hu et al ask whether the sometimes self-limiting nature of PPP could help to explain the lack of significant difference in the primary endpoint of our study. We consider this a possibility and have acknowledged the fact that variations in PPP disease severity over time could have masked a treatment effect of spesolimab during the trial [ 1 ]. As Hu et al mention, demonstrating a significant difference between a trial drug and placebo in PPP trials is indeed challenging because of the disease course.…”

“…As Hu et al mention, demonstrating a significant difference between a trial drug and placebo in PPP trials is indeed challenging because of the disease course. In our trial, methods to minimise natural disease improvement concealing a potential treatment effect of spesolimab were implemented, such as excluding patients with a PPP Area and Severity Index (PPP ASI) total reduction ≥ 5 between screening and baseline [ 1 ]. While it is possible that the primary endpoint at Week 16 may have coincided with natural disease improvement in some subjects, improvements in severity scores in the placebo arm were only modest.…”