Secukinumab Reverses Disease‐Defining Psoriasis Histopathology While Retaining Full T‐cell Activation Potential

Abstract

Secukinumab is an anti‐IL‐17A fully human monoclonal antibody with clinical efficacy in psoriasis. The effects of secukinumab on skin pathology and T cell activation were investigated. In a randomized double‐blinded placebo controlled study, subjects with chronic plaque‐type psoriasis received 300 mg s.c. secukinumab (n=24) or placebo (n=12) at Weeks 0, 1, 2, 3 and 4, then every 4 weeks until Week 12. Biopsies of lesional and non‐lesional skin were assessed for epidermal growth, differentiation / maturation, mitotic rate, infiltrating T‐cells, macrophages, and dendritic cell (DC) subsets. The primary endpoint was histological disease reversal at Week 12. Circulating T‐cells were evaluated by flow cytometry for the activation marker CD69. 14/23 secukinumab‐treated (61%) and 0/12 (0%) placebo‐treated subjects attained histologic disease reversal at Week 12 (p<0.001; secukinumab vs. placebo). 14/24 (58.3%) secukinumab‐treated and 0/12 (0%) placebo‐treated subjects had a PASI90 response at Week 12. Histological disease reversal was correlated with PASI score at Week 12 (r= ‐0.77, p <0.001). T‐cells, macrophages, and myeloid DC subsets were reduced by secukinumab in lesional skin, but resident immune cell populations were retained. Ex vivo, 48% of circulating T‐cells induced CD69 before vs. 46% after secukinumab treatment (p=ns). Secukinumab treatment significantly reversed skin histopathology of psoriasis while reducing pathologic infiltration by T‐cells, macrophages, and DC subsets; responses to global T‐cell activation were unimpaired. Funded by Novartis.