IL-22RA1 inhibition shows potential in atopic dermatitis

Comparing the IL-22 receptor subunit alpha-1 (RA1) inhibitor temtokibart with dupilumab using single-cell sequencing and molecular analysis revealed different effect patterns but similar outcomes in reducing Eczema Area and Severity Index (EASI) score and itch numeric rating scale (NRS) in a small, phase 2, mechanism-of-action trial.

Increased IL-22 expression in atopic dermatitis (AD) is implicated in epidermal hyperplasia and decreased skin barrier [1–3]. “Our group recently found that IL-22 is also involved in a side effect of dupilumab, the dupilumab-associated head-neck dermatitis,” Dr Christine Bangert (Medical University Vienna, Austria) added [3]. A tighter control of IL-22 expression might be important in patients with AD, upstream from dupilumab mechanism-of-action. Dr Bangert presented a phase 2a mode-of-action trial on the novel IL-22RA1 blocker temtokibart. “It blocks the IL-22RA1 subunit of the IL-22 receptor and thereby inhibits signalling of IL22, but that's not its only modeof action: it's also part of the IL-20 receptor type 2 and inhibits the signalling of IL-20 and IL-24 as recent in vitro data has shown. However, the type 1 IL-20 receptor is not affected by temtokibart,” Dr Bangert explained the compounds.

The 12 adult participants with moderate-to-severe AD were randomised 2:1 to 450 mg of temtokibart by subcutaneous injection or 300 mg of dupilumab, both given every second week over 16 weeks. Skin biopsies for single-cell sequencing and tape stripping for the molecular analysis of the skin barrier plus stratum corneum metabolites were taken at weeks 0, 1, 4, and 16.

From week 1 to week 16, both agents showed similar reductions in EASI score and itch-NRS reductions. The safety assessment showed adverse events in 88.9% of the temtokibart and 75% of the dupilumab participants but no serious adverse events or adverse events leading to discontinuation of the study. On temtokibart, 8 participants had a mild and 1 participant had a moderate adverse events, among these were 3 cases of atopic dermatitis that resolved without medication.

Single-cell RNA sequencing found that IL-22RA1 is mainly expressed in keratinocytes. “We clearly see an improvement of keratin 1 and 10, which are involved in the barrier homeostasis, already after 2 weeks of treatment with temtokibart; we don't see this effect with dupilumab,” Dr Bangert said. She further pointed to an increase in barrier-improving molecules like desmoglein1, desmocollin, and claudin1 that was also only present in the temtokibart group. A reduction in pro-inflammatory S100 metabolites was similarly induced by both drugs but had a faster onset in the temtokibart recipients.

A further analysis of changes in the natural moisturising factors urocanic acid and pyrrolidone carboxylic acid revealed a statistically significant increase from baseline in the temtokibart group as of week 1 (P<0.0001 for both comparisons). “We see a less pronounced effect with dupilumab and only at a later timepoint,” Dr Bangert added.

Dupilumab and temtokibart differed in their effects on AD cytokines. Dupilumab reduced IL-4R, downregulated thymus and activation-regulated chemokine (TARC), while upregulating markers of type 1 associated mediators after 1 week. In contrast, temtokibart did not seem to affect innate, type 1, or type 2 (e.g. TARC) chemokines.

Dr Bangert summarised that temtokibart has a primary effect on the skin barrier and probably an indirect effect on the immune cells at a later stage.

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   1. Ungar B, et al J Invest Dermatol. 2017;137(3):603-613.
   2. Fujita H. J Dermatol Sci. 2013;72(1):3-8.
   3. Bangert C, et al. Targeting IL-22RA1 with temtokibart in patients with moderate to severe atopic dermatitis induces fast clinical and molecular responses, distinct from dupilumab. 3, EADV Congress 2024, 25–28 September, Amsterdam, the Netherlands.

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Posted on 6 November 20246 November 2024