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Results from the KNOCKOUT trial show high induction doses of the IL-23 blocker risankizumab led to a marked reduction in resident memory T cells.

In the KNOCKOUT trial, high induction doses of the IL-23 blocker risankizumab led to a marked reduction in resident memory T cells even 36 weeks after researchers applied the last dose. This could explain the long durability of skin clearance in patients with psoriasis treated with an IL-23 inhibitor.

Clinical experience shows psoriatic lesions often recur in the same anatomical locations, driven by resident memory T (T_RM) cells. IL-23 plays an essential role in psoriasis pathogenesis and T_RM cell retention and proliferation. The KNOCKOUT study (NCT05283135) is an ongoing phase 2 study in patients with moderate-to-severe psoriasis that uses high doses of risankizumab (300 mg and 600 mg) to induce long-term remission by decreasing T_RM cell number in skin affected by psoriasis. The primary endpoint of the KNOCKOUT trial is the reduction in the number of T_RM cells between baseline and week 52 with high doses of the IL-23 inhibitor risankizumab. Moreover, the clinical efficacy and safety of high induction doses of risankizumab were evaluated as secondary endpoints.

All 20 participants were treated with 300 mg or 600 mg risankizumab at weeks 0, 4, and 16, with no further treatment; 16 participants completed the week 52 visit. The study team assessed the differential distribution of T cell sub-clusters from baseline lesional skin, nonlesional skin, and post-treatment lesional skin with single-cell RNA gene sequence analysis.

The results demonstrated that high induction doses of risankizumab led to a marked reduction in epidermal T_RM cells. Moreover, lesional inflammatory cells at week 52 returned to levels observed in baseline non-lesional skin with significant reductions in T_RM cells. Risankizumab was also well tolerated, and researchers observed no new safety signals.

As Andrew Blauvelt, MD, MBA, concluded, the T_RM reductions noted with high induction dosing of risankizumab may explain the durability of skin clearance noted in patients with moderate-to-severe psoriasis on a cellular level. Larger prospective studies are needed to confirm these results.

Medical writing support was provided by Dr. Susanne Kammerer.
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