FC23 High induction dosing of risankizumab in patients with moderate-to-severe plaque leads to marked suppression of resident memory T cell number and function in resolved psoriatic skin

Abstract Risankizumab, a humanized monoclonal antibody that specifically inhibits IL-23, is approved to treat moderate-to-severe plaque psoriasis. In Phase 2, double-blinded, single-centre KNOCKOUT (NCT05283135) study, we evaluated higher-than-approved risankizumab induction doses (300 and 600 mg) for efficacy measures and modulation of lesional resident memory T cells (TRM), cells responsible for psoriasis recurrences. A total of 20 patients were enrolled, and 16 patients completed Week 52. Patients were randomized 1:1 to receive subcutaneous risankizumab 300 or 600 mg at Weeks 0, 4, and 16, with no further dosing. Static Physician’s Global Assessment (sPGA) was monitored throughout the study and reported here with modified non-responder imputation. At Week 16, 94.4% [n = 17, 95% confidence interval, CI (72.7, 99.9)] of all patients achieved sPGA 0/1 and 66.7% [n = 12, 95% CI (41.0, 86.7)] achieved sPGA 0. At Week 52, 36 weeks after the last dose, sPGA 0/1 and sPGA 0 responses were achieved by 61.1% [n = 11, 95% CI (35.7, 82.7)] and 44.4% [n = 8, 95% CI (21.5, 69.2)] of all patients, respectively. We also performed single-cell RNA-sequencing of biopsy samples at baseline and at Week 52 from both dose groups. In lesions of patients receiving the higher dose (600 mg) of risankizumab, the number of CD8+ tissue-resident memory T (TRM) cells was markedly reduced, with more marked suppression of the intercellular communication network between TRM and keratinocytes compared with the lower dose (300 mg) group. A shift towards increased crosstalk between Tregs and TRM, was noted, particularly in the 600 mg dose group. Mechanistically, the IL-23 blockade also impaired the expression of IL15 and IL7 in keratinocytes, which are known survival factors for CD8+ TRM. Furthermore, keratinocyte-derived TNFSF15 (TL1A), a known inflammatory signal for TH17 maintenance, was strongly attenuated in the 600 mg dose group compared with the 300 mg dose group. These findings suggest that the high and prolonged therapeutic clinical responses seen with high induction doses of risankizumab may be explained by the marked suppression of TRM number and function.