Durable skin clearance by IL-23 blockers due to reduction of resident memory T cells

In the KNOCKOUT trial, high induction doses of the IL-23 blocker risankizumab led to a significant decrease in resident memory T cells even 36 weeks after the final dosage. This reduction could potentially account for the sustained improvement in skin clearance seen in patients with psoriasis treated with IL-23 inhibitors.

As Prof. Andrew Blauvelt (Oregon Medical Research Center, OR, USA) pointed out, data suggests that one should “hit hard and early” in psoriasis to induce remission [1,2]. One strategy is to target tissue-resident memory cells (T_RM cells). These cells are responsible for psoriasis recurrences at the same sites as previous disease [3]. IL-23 plays an essential role not only in psoriasis pathogenesis but also in T_RM cell retention and proliferation.

The KNOCKOUT study (NCT05283135) is an ongoing phase 2 study including patients with moderate-to-severe psoriasis receiving 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 [1]. The primary endpoint of the KNOCKOUT trial is the reduction in the number of T_RM cells between baseline and week 52 with these doses of the IL-23 inhibitor. Secondary endpoints evaluated are the clinical efficacy and safety of high induction doses of risankizumab.

All 20 participants were treated with 300 mg or 600 mg risankizumab at weeks 0, 4, and 16, with no further treatment. The 52-week visit was completed by 16 participants. Differential distribution of T-cell subclusters from baseline lesional skin, baseline non-lesional skin, and post-treatment lesional skin were assessed with single-cell RNA sequencing analysis.

The results demonstrated that high induction doses of risankizumab led to a marked reduction in the number of epidermal T_RM cells (see Figure). Moreover, lesional inflammatory cells at week 52 returned to levels of T_RM cells observed in baseline non-lesional skin. Risankizumab also proved to be well tolerated, and no new safety signals were observed.

Figure: Significant reduction in T_RM cells with high induction risankizumab at week 52 [2]

TRM, tissue-resident memory cells. Lesional baseline (n=13), non-lesional baseline (n=12), and post-treatment low-dose (n=8), and high-dose (n=5) groups.

Prof. Blauvelt concluded that 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.

Relevant readings:

• Interview: Meet the Trialist Dr Andrew Blauvelt
• Knocking out psoriasis with high-dose risankizumab? (WCD 2023)

1. 
   
   1. Blauvelt A, et al. High induction dosing of risankizumab in patients with moderate-to-severe plaque psoriasis: 52 week results from the phase 2 KNOCKOUT study. LB1, 2024 AAD Annual Meeting, 8–12 March, San Diego, CA, USA.
   2. Schäkel K, et al. GUIDE trial results after withdrawal in part 3: Long-term remission in patients with psoriasis treated with guselkumab within 15 months from onset of symptoms. P50236, 2024 AAD Annual Meeting, 8­–12 March, San Diego, USA.
   3. Blauvelt A, et al. J Psoriasis Pso Arthr 2022;7:157-159.

Copyright ©2024 Medicom Medical Publishers



Posted on 22 April, 202422 April, 2024