Tralokinumab treatment may neutralize IL-13 in patients with atopic dermatitis

Key takeaways:

• Tralokinumab normalized expression of AD biomarkers in serum and lesional skin.
• Tralokinumab improved epidermal pathology and reduced inflammatory mediators and abnormal skin barrier markers.

Tralokinumab improved epidermal pathology, reduced inflammation and changed significant skin biomarkers in patients with atopic dermatitis, according to a study published in The European Journal of Allergy and Clinical Immunology.

“We wanted to understand the mechanism of action of tralokinumab in atopic dermatitis (AD) and how it changes the skin phenotype back to that of visibly normal skin,” Emma Guttman-Yassky, MD, PhD, Waldman Professor of Dermatology and system chair of the Kimberly and Eric J. Waldman Department of Dermatology at Icahn School of Medicine at Mount Sinai, told Healio.

Emma Guttman-Yassky

“We also wanted to see how biomarkers correlate with clinical responses,” said Guttman-Yassky, who also is a member of the Healio Asthma/Allergy Peer Perspective Board.

Methods

Guttman-Yassky and colleagues evaluated skin biopsies and blood samples of patients from the phase 3 ECZTRA 1 study and the open-label ECZTEND extension trial.

The 52-week multinational, randomized, double-blind, placebo-controlled ECZTRA 1 trial included adults with moderate to severe AD. The patients were randomized in a 3:1 ratio including a group that took tralokinumab 300 mg subcutaneously after a 600 mg initial dose on day 0 or the control group that took a placebo every other week for 16 weeks. After week 16, patients who took tralokinumab and achieved clinical responses were re-randomized 2:2:1 to tralokinumab every 2 or 4 weeks or placebo for a 36-week period.

The ongoing, 5-year, open label, single arm, multicenter, long-term ECZTEND extension trial includes those patients who completed previous tralokinumab trials. Those who participated in the ECZTEND trial were given 300 mg of tralokinumab subcutaneously every 2 weeks after an initial 600 mg dose.

Researchers’ endpoints included AD extent, severity and number of patients improving in the Eczema Area and Severity Index (EASI-75) from baseline. Patients were also evaluated with the Numeric Rating Scale (NRS) on improvement in worst weekly pruritus from baseline.

Patients’ blood samples were collected at baseline as well as at weeks 4, 8 and 16. Skin biopsy samples were also collected from lesional and non-lesional skin at baseline and then 2 years after treatment with tralokinumab. Biopsies were collected from lesional skin at week 4 and 16 of treatment.

Results

While all patients (n = 802; mean age, 38.8) had their blood collected, only 299 patients from ECZTRA 1 (n = 223, tralokinumab; n = 76, placebo) were included in the analyses.

Among those with analyzed serum samples, 50 patients (n = 35, tralokinumab; n = 15, placebo) also donated skin biopsies. From those patients, 13 who were treated with tralokinumab in ECZTRA 1 and ECZTEND provided skin samples after 2 years of treatment.

Levels of serum biomarkers IL-13 and IL-22 were elevated at baseline with 86% having an IgE level above 150 IU/mL, compared with reference values in healthy controls. Guttman-Yassky and colleagues also found a positive correlation between serum levels of IL-13 and CCL17/TARC, periostin and IL-22.

Baseline EASI was correlated with serum levels of all four molecules. Decreased serum levels from baseline were found after tralokinumab treatment of type 2 biomarkers CCL17/TARC, periostin and IgE by week 4 and further by week 16. Similar findings occurred with IL-22 serum levels.

Compared with placebo, the change from baseline to week 16 after treatment with tralokinumab was significantly greater in all four serum biomarkers. Improvements in EASI and purities NRS were also seen at week 16 when compared with the placebo group. From baseline to week 16, the change in EASI was correlated with changes in serum CCL17/TARC, periostin and IL-22.

Compared with non-lesional biopsies, lesional biopsies showed increased epidermal hyperplasia at baseline. Compared with baseline, at week 16, tralokinumab treatment showed a significantly reduced epidermal thickness and reduced expression of cell proliferation markers CK16 and Ki-67.

Improvements in epidermal hyperplasia were significantly greater in the tralokinumab group than in the placebo group. The expression of S100A7 and CD11c were also significantly reduced in the tralokinumab group as well as an increased coverage of the skin barrier protein loricrin in lesions at week 16 compared with baseline.

RNA sequencing identified 1,908 genes that were differentially expressed between lesional and non-lesional skin at baseline. Patients receiving tralokinumab (n = 35) showed increased improvement toward a non-lesional profile, but patients on placebo (n = 15) did not, at 16 weeks of treatment.

Researchers found altered gene expression by week 4 of tralokinumab treatment, while at week 16, the genes dysregulated in AD improved 46.6% in the treatment group compared with 16.4% in the placebo group. At week 16, tralokinumab patients’ gene expression approached non-lesional levels.

Among the group of tralokinumab-treated patients with biopsy data from week 16 and 3 years (n = 13), 1,274 differentially expressed genes were identified between lesional and non-lesional skin at baseline

In this same group, a 39% improvement of genes dysregulated in AD was seen in those taking tralokinumab at week 16, and 85% at 2 years compared with 15% more lesional phenotype in patients in the placebo group. At 2 years, tralokinumab also modified the transcriptomic profile of non-lesional skin and improved EASI and pruritus NRS.

“It takes some time to fully change the phenotype of AD, but there is progressive and continuous improvement after 16 weeks of treatment to 2 years of use of tralokinumab,” Guttman-Yassky said.

“We need to remember that AD is a chronic disease that patients have for a long time, and it takes time to reverse it. Thus, I advise patients and doctors to allow treatments adequate time before they determine if they work,” she continued.

Using gene set enrichment analysis, researchers found that the impact of tralokinumab relative to placebo related to key immune pathways. At week 16, patients in the tralokinumab group compared with the placebo group had significant decreases in the mean expression of Th22/IL-22, and Th17 gene signatures in lesional skin. Tralokinumab also shifted the expression of type 2 markers in lesional skin such as CCL18, CCL22 and IL4R into non-lesional skin levels.

The 2-year subgroup that provided skin samples at the 2-year mark showed that tralokinumab treatment continued to modulate gene expression in Th cell function with further shifts into non-lesional profiles. After 2 years, the expression of genes downregulated in the Th2 pathway (IL4R, IL31, CCL17 and CCL26), the Th1 pathway gene IFNG, and the Th17 and Th22 pathway genes (IL22, S100A7, S100A8, and S100A9).

At 2 years, tralokinumab also decreased the expression of the itch-associated cytokine gene IL31. It additionally led to an increased expression of epidermal differentiation and barrier genes CLDN1 and LOR and shifted atherosclerosis signaling pathway genes SELE, IL-37 and S100A8 toward non-lesional expression.

Lesional skin saw significant reductions in MMP12, PI3, IL4R, CCL17, CCL18, IL13, S100A7, and S100A8 whereas FLG expression increased and IFNG decreased in non-lesional skin.

“We see after 2 years of use of a single cytokine targeting agent a normalization of the AD phenotype towards non-lesional skin,” Guttman-Yassky said. “Among genes that were reversed with tralokinumab were immune genes, barrier genes and also genes associated with cardiovascular disease.”

Guttman-Yassky said that tralokinumab is different from other AD treatments because it is a single cytokine targeting agent with a clean safety profile. This study proves that the IL-13 cytokine is central to the pathogenesis of AD, she added.

“It takes time for the full or almost full normalization of the skin and highlights the correlation between the skin ‘healing’ and the reduction of the inflammation in AD with effective treatment,” she said. “Future studies should evaluate various AD cohorts based on ethnicity and other characteristics.”