Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double-blind, placebo-controlled Phase 2 trial.

Autor: Weiss A; UNION Therapeutics, Hellerup, Denmark.; Novo Nordisk Foundation for Biosustainability, Technical University of Denmark, Lyngby, Denmark., Delavenne E; UNION Therapeutics, Hellerup, Denmark., Matias C; UNION Therapeutics, Hellerup, Denmark., Lagler H; Department of Medicine 1, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Wien, Austria., Simon D; UNION Therapeutics, Hellerup, Denmark., Li P; UNION Therapeutics, Hellerup, Denmark., Hansen JU; Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark., Dos Santos TP; Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark., Jana B; Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark., Priemel P; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark., Bangert C; Department of Dermatology, Medical University of Vienna, Wien, Austria., Bauer M; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Eberl S; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Nussbaumer-Pröll A; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Anne Österreicher Z; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Matzneller P; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Quint T; Department of Dermatology, Medical University of Vienna, Wien, Austria., Weber M; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Nielsen HM; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark., Rades T; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark., Johansen HK; Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Westh H; Hvidovre Hospital, Hvidovre, Denmark., Kim W; Warren Alpert Medical School of Brown University, Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island, USA., Mylonakis E; Warren Alpert Medical School of Brown University, Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island, USA., Friis C; Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark., Guardabassi L; Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark., Pace J; UNION Therapeutics, Hellerup, Denmark., Lundberg CV; Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark., M'Zali F; University of Bordeaux, Bordeaux Cede., Butty P; CEVA Santé Animale, Libourne, France., Sørensen N; Clinical Microbiomics, Copenhagen, Denmark., Nielsen HB; Clinical Microbiomics, Copenhagen, Denmark., Toft-Kehler R; UNION Therapeutics, Hellerup, Denmark., Guttman-Yassky E; Icahn School of Medicine at Mount Sinai, New York, New York, USA., Stingl G; Department of Dermatology, Medical University of Vienna, Wien, Austria., Zeitlinger M; Department of Clinical Pharmacology, Medical University of Vienna, Wien, Austria., Sommer M; UNION Therapeutics, Hellerup, Denmark.; Novo Nordisk Foundation for Biosustainability, Technical University of Denmark, Lyngby, Denmark.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2022 May; Vol. 12 (5), pp. e790.
DOI: 10.1002/ctm2.790
Abstrakt: Background: In patients with atopic dermatitis (AD), Staphylococcus aureus frequently colonizes lesions and is hypothesized to be linked to disease severity and progression. Treatments that reduce S. aureus colonization without significantly affecting the skin commensal microbiota are needed.
Methods and Findings: In this study, we tested ATx201 (niclosamide), a small molecule, on its efficacy to reduce S. aureus and propensity to evolve resistance in vitro. Various cutaneous formulations were then tested in a superficial skin infection model. Finally, a Phase 2 randomized, double-blind and placebo-controlled trial was performed to investigate the impact of ATx201 OINTMENT 2% on S. aureus colonization and skin microbiome composition in patients with mild-to-severe AD (EudraCT:2016-003501-33). ATx201 has a narrow minimal inhibitory concentration distribution (.125-.5 μg/ml) consistent with its mode of action - targeting the proton motive force effectively stopping cell growth. In murine models, ATx201 can effectively treat superficial skin infections of methicillin-resistant S. aureus. In a Phase 2 trial in patients with mild-to-severe AD (N = 36), twice-daily treatment with ATx201 OINTMENT 2% effectively reduces S. aureus colonization in quantitative colony forming unit (CFU) analysis (primary endpoint: 94.4% active vs. 38.9% vehicle success rate, p = .0016) and increases the Shannon diversity of the skin microbiome at day 7 significantly compared to vehicle.
Conclusion: These results suggest that ATx201 could become a new treatment modality as a decolonizing agent.
(© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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