Secukinumab versus guselkumab in the complete resolution of ustekinumab‐resistant psoriatic plaques: The ARROW study

Abstract

AbstractInterleukin (IL)‐23–independent IL‐17A production has been suggested to be involved in persistent manifestations of psoriatic disease, including anti–IL‐12/23–refractory psoriatic plaques; this study aimed to test this hypothesis by investigating the clinical and molecular effects of direct IL‐17A (with secukinumab) versus selective IL‐23 inhibition (with guselkumab) in patients with anti–IL‐12/23 (ustekinumab)–refractory psoriatic plaques. A 16‐week, randomized, open‐label, parallel‐group, Phase IIa study (ARROW, NCT03553823) was conducted in patients with ≥1 active psoriatic plaque (total clinical score [TCS] ≥6) at screening despite treatment with ustekinumab, and a Psoriasis Area and Severity Index (PASI) score 1–10. Patients were randomized 1:1 to receive secukinumab 300 mg (n = 20) or guselkumab 100 mg (n = 20). Biopsies from one refractory (‘target plaque’) were obtained at baseline and Week 16. The primary endpoint was the proportion of patients whose ustekinumab‐refractory target plaque achieved clear/almost clear status (TCS 0–2) at Week 16. Transcriptomic and histological analyses were conducted on target plaques to determine the molecular effects of direct IL‐17A versus selective IL‐23 inhibition. At Week 16, target plaque clear/almost clear status was achieved in 60.0% of patients treated with secukinumab versus 40.0% of patients treated with guselkumab (p = 0.1715). Molecular analyses identified that secukinumab modulated a greater proportion of psoriasis disease transcriptome genes (72.1% vs. 48.0%) and resulted in more histological responders (72.2% vs. 53.3%) compared with guselkumab. Secukinumab demonstrated a greater clinical and molecular effect on ustekinumab‐refractory psoriatic plaques versus guselkumab. These results are consistent with the hypothesis that IL‐23–independent IL‐17 mechanisms may be relevant to the inflammation driving refractory manifestations of psoriasis.