Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial

Tali Czarnowicki; Anders B Dohlman; Kunal Malik; Diane Antonini; Robert Bissonnette; Tom C Chan; Lisa Zhou; Huei-Chi Wen; Yeriel Estrada; Hui Xu; Catherine Bryson; Jie Shen; Deepak Lala; Avi Ma'ayan; Gerard McGeehan; Richard Gregg; Emma Guttman-Yassky

doi:10.1016/j.anai.2018.03.013

Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial

Ann Allergy Asthma Immunol. 2018 Jun;120(6):631-640.e11. doi: 10.1016/j.anai.2018.03.013. Epub 2018 Mar 19.

Authors

Tali Czarnowicki¹, Anders B Dohlman², Kunal Malik³, Diane Antonini⁴, Robert Bissonnette⁵, Tom C Chan⁶, Lisa Zhou⁶, Huei-Chi Wen⁶, Yeriel Estrada⁶, Hui Xu⁶, Catherine Bryson⁴, Jie Shen⁷, Deepak Lala⁴, Avi Ma'ayan², Gerard McGeehan⁴, Richard Gregg⁴, Emma Guttman-Yassky⁸

Affiliations

¹ Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York.
² Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, BD2K-LINCS Data Coordination and Integration Center, Icahn School of Medicine at Mount Sinai School, New York, New York.
³ Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; College of Medicine, SUNY Downstate, Brooklyn, New York.
⁴ Vitae Pharmaceuticals Inc, an Allergan affiliate, Irvine, California.
⁵ Innovaderm Research Inc, Montreal, Quebec, Canada.
⁶ Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
⁷ Allergan plc, Irvine, California.
⁸ Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York. Electronic address: emma.guttman@mountsinai.org.

PMID: 29567358
DOI: 10.1016/j.anai.2018.03.013

Abstract

Background: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems.

Objective: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD).

Methods: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and posttreatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated.

Results: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P = .02) and lipid (adenosine triphosphate-binding cassette subfamily G member 1 and sterol regulatory element binding protein 1c, P < .01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 nonsignificantly suppressed cellular infiltrates and down-regulated mRNA expression of several T_H17/T_H22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers.

Conclusion: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities.

Trial registration: clinicaltrials.gov Identifier: NCT02655679.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / immunology
Administration, Cutaneous
Adult
Anti-Inflammatory Agents / therapeutic use*
Biological Transport / drug effects
Biological Transport / immunology
Dermatitis, Atopic / drug therapy*
Dermatitis, Atopic / genetics
Dermatitis, Atopic / immunology
Dermatitis, Atopic / pathology
Double-Blind Method
Epidermis / drug effects*
Epidermis / immunology
Epidermis / pathology
Female
Filaggrin Proteins
Gene Expression Regulation / immunology
Humans
Immunologic Factors / therapeutic use*
Interleukin-6 / genetics
Interleukin-6 / immunology
Intermediate Filament Proteins / genetics
Intermediate Filament Proteins / immunology
Keratin-16 / genetics
Keratin-16 / immunology
Liver X Receptors / agonists*
Liver X Receptors / genetics
Liver X Receptors / immunology
Male
Membrane Proteins / genetics
Membrane Proteins / immunology
Middle Aged
RNA, Messenger / agonists*
RNA, Messenger / genetics
RNA, Messenger / immunology
S100A12 Protein / genetics
S100A12 Protein / immunology
Severity of Illness Index
Sterol Regulatory Element Binding Protein 1 / genetics
Sterol Regulatory Element Binding Protein 1 / immunology
Treatment Outcome

Substances

ATP-Binding Cassette Transporters
Anti-Inflammatory Agents
FLG protein, human
Filaggrin Proteins
IL6 protein, human
Immunologic Factors
Interleukin-6
Intermediate Filament Proteins
KRT16 protein, human
Keratin-16
Liver X Receptors
Membrane Proteins
RNA, Messenger
S100A12 Protein
S100A12 protein, human
Sterol Regulatory Element Binding Protein 1
loricrin

Associated data

ClinicalTrials.gov/NCT02655679