NEW YORK — Already in late-stage clinical trials, temtokibart, an interleukin (IL)-22 inhibitor, has demonstrated broad activity against multiple markers of inflammation, pruritus, and impaired barrier function associated with atopic dermatitis (AD), according to separate studies of its impact on molecular signaling by independent investigators.

In a biopsy substudy of a phase 2b randomized trial, the immune subset of transcriptomic markers involved “a 97% shift” toward that of normal skin, according to Ester Del Duca, MD, PhD, a researcher with academic appointments at the Icahn School of Medicine at Mount Sinai in New York City and Sapienza University of Rome, Rome, Italy.

In a second study, which compared skin biopsies from patients with AD taking temtokibart, which is administered subcutaneously, with those taking the IL-4 inhibitor dupilumab, there were striking differences at the molecular level with generally broader anti-inflammatory activities associated with temtokibart, according to Christine Bangert, MD, a senior dermatologist at the Medical University of Vienna, Vienna, Austria.

IL-22 Target Is Attractive for AD

Both studies, which were presented consecutively at the Sixth Inflammatory Skin Disease Summit, associated temtokibart with inhibition of multiple molecular pathways of AD pathophysiology, suggesting the potential for broad control of AD symptoms.

The study presented by Del Duca was based on a subset of 22 patients participating in a dose-ranging phase 2b placebo-controlled randomized trial. Changes in the transcriptomic profiles of the lesional and nonlesional skin were compared at baseline and at the end of 14 weeks.

Relative to nonlesional skin, the changes in lesional skin over the study period included downregulation of T helper (Th) axes in the Th17/22 cascade, including the IL-22, IL-17A/F, and S100A7/8/9 pathways, as well as downregulation of cytokines and chemokines associated with Th2, such as IL-4, IL-13, and CCL17, and with Th1, such as interferon gamma and CXCL9-11, Del Duca reported.

In addition, there was downregulation of molecular biomarkers of pruritus, such as HRH1/2, HTR2A, and oncostatin M. Biomarkers associated with skin barrier function, including those in the CLDN gene family, cadherins, and genes involved in epidermal metabolism, were upregulated.

In the substudy, changes in inflammatory biomarkers positively correlated with improvement in Eczema Area and Severity Index (EASI) scores (P < .05) and with improvements in patient-reported outcomes such as the Dermatology Life Quality Index (P < .05), Del Duca said.

In the single-center study presented by Bangert, changes in biomarkers from baseline were compared in eight patients with AD treated with temtokibart (600 mg) and four patients treated with dupilumab (300 mg) by injection every 2 weeks. Punch biopsies were taken at weeks 0, 1, 4, and 16, Bangert reported.

From a baseline EASI score of 40, the median skin clearance climbed to an EASI score of just < 75 in the temtokibart group and slightly > 80 in the dupilumab group by week 16. These scores were similar, but the improvement in the Numerical Rating Scale for itch was comparable, with half of the patients in both treatment groups achieving an itch reduction of more than four points.

Inflammatory Response to Monoclonal Antibodies Differs

The clinical findings were consistent with the molecular findings, which showed antibody-specific differences in regulation of AD disease markers in skin lymphocytes. For example, the IL-4 receptor alpha gene was downregulated by dupilumab but unaffected in those treated with temtokibart, according to Bangert.

Conversely, although interferon gamma expression was increased from baseline in patients treated with dupilumab, it was unchanged in patients treated with temtokibart.

Relative to dupilumab, temtokibart was associated with improvement in expression of barrier function genes, such as KRT1 and KRT10, as well as barrier integrity, as represented by cell adhesion molecules such as DSC1 and CLDN1. Temtokibart also provided faster reduction of proinflammatory S100s, even within the first week.

Previous work has shown that IL-22 receptor subunit alpha 1 is expressed predominantly in keratinocytes rather than in immune cells, Bangert said. The interaction of keratinocytes and fibroblasts using the regulatory ACTIVIN pathway might explain why this targeted therapy is more closely associated with an increase in regulatory T cells. Using FOXP3 staining to gauge this increase, Bangert reported a marked increase in FOXP3 positive cells from baseline with temtokibart but no change with dupilumab.

Temtokibart and dupilumab appear to control AD through different effects on molecular signaling, according to the data that Bangert presented. On transcriptomic analysis, there were differences not only in effects on proinflammatory cytokines but also on pathways affecting barrier function and itch.

Results from the latter study suggest that keratinocytes might be an important target for AD therapy, James Krueger, MD, PhD, head of the Laboratory for Investigative Dermatology at Rockefeller University in New York City, said at the meeting. He called the apparent ability to communicate with the immune system, as reported by Bangert, “provocative.”

Although both studies had a small number of patients, limiting the ability to draw definitive conclusions, Krueger said they both reveal that “there is something really, really remarkable here” with regard to the potential for temtokibart to promote crosstalk in order to restore normal immune function, not just downregulate the inflammatory response.

The phase 2b study was supported by LEO Pharma, which is developing temtokibart. Del Duca reported no potential conflicts of interest. LEO has provided research funding for Bangert, who also has financial relationships with AbbVie, ALK, Almirall, Eli Lilly, Galderma, Genzyme, Mylan, Novartis, Pfizer, Sanofi, Sun Pharma, and UCB.