The Show Must Go On

An Update on Clinical Experiences and Clinical Studies on Novel Pharmaceutical Developments for the Treatment of Atopic Dermatitis

Tatjana Honstein; Thomas Werfel

Disclosures

Curr Opin Allergy Clin Immunol. 2020;20(4):386-394. 

In This Article

Targeting IL-13 for the Treatment of Atopic Dermatitis With Tralokinumab or Lebrikizumab

IL-13 is a central therapeutical target of Th2-driven diseases. It has many common functional properties to IL-4 as it binds to IL-13Rα containing the same α subunit of the heterodimeric IL-4 receptor. In contrast to dupilumab, the anti-IL-13 antibody tralokinumab and lebrikizumab do not bind to the receptor but neutralize the IL-13 cytokine directly. Moreover, IL-13 has no stimulating effects on T lymphocytes in contrast to IL-4. Interestingly, the binding sites of tralokinumab and lebrikizumab are located at opposite side of the IL-13 molecule, which leads to different blocking effects: Although lebrikizumab blocks the binding of IL-13 exclusively to the IL-13Rα1, tralokinumab also inhibits the binding of IL-13 to IL-13Rα2.[24] The latter receptor molecule is considered to function mainly as a negative regulator of IL-13 functions although a few observations support the notion that it may also be involved in stimulating cells (mainly fibroblasts) after internalization of the receptor together with its ligand. A recently published study based on deeply sequenced transcriptomes of 147 atopic dermatitis patients and their in-depth analysis showed a disease-specific molecular signature characterized by a dominant IL-13-signaling pathway and poorly detectable IL-4.[25]

A phase IIb study in a randomized, placebo-controlled group of 204 individuals with severe-to-moderate atopic dermatitis demonstrated the efficacy and safety of tralokinumab. The treatment was administered subcutaneously with different doses for 3 months. The best improvements were observed in the highest dosing group receiving 300 mg antibody. Seventy-three percent of these patients showed a reduction of 50% of the skin severity score EASI ('EASI50') compared with 52% in the placebo group and 43% compared with 16% showed a reduction of 75% ('EASI75'). A positive development of the numerical evaluation scale for itching and the dermatological quality of life index could also be documented. Additionally, a treatment response by means of biomarkers in the blood (DPP4, periostin, TARC, and IgE) was also observed. Upper respiratory tract infections and headache were the most common adverse events. So far, there were fewer treatment-associated cases of conjunctivitis in tralokinumab trials compared with dupilumab trials but of course no head-to-head comparisons are available so far.[26] Tralokinumab also met all primary and secondary endpoints in three phase III studies for the treatment of moderate-to-severe atopic dermatitis in adults, which have so far been communicated in press releases and on conferences.

In a proof-of-concept study with the anti-IL-13 antibody lebrikizumab a significant, but not very pronounced improvement of the eczema score was observed after 12 weeks of monthly treatment.[27] Responses in the placebo group were so high that possible therapeutic effects of the antibody may have been partially masked by topical corticosteroids, which could be applied by the patients in this study. Steroid effects were avoided more in a recent phase II trial with lebrikizumab. and the results of the antibody were more convincing than in the first study.[28] After 16 weeks EASI75 was observed 24% of the study patients in the placebo group compared with 43%, 56 or 61% after the application of 125 mg lebrikizumab every 4 weeks, 250 mg every 4 weeks or 250 mg every 2 weeks. Conjunctivitis as treatment emergent adverse event was observed in 2.6% of all patients in the treatment groups and not in the placebo group.

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