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

Abstract

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.

Microbial manipulation in atopic dermatitis

“…However, Weiss et al., 16 aim to succeed where prior anti‐ S. aureus strategies have failed through several unique innovations. In their study, the authors demonstrated the potent anti‐ staphylococcal activity of niclosamide, a traditional antihelminthic drug.…”

“…3,14 Furthermore, attempting to curtail S. aureus through topical use of CoNS-containing probiotics 3 presents an experimental risk of infecting patients with the treatment strain. 15 However, Weiss et al, 16 aim to succeed where prior anti-S. aureus strategies have failed through several unique innovations. In their study, the authors demonstrated the potent anti-staphylococcal activity of niclosamide, a traditional antihelminthic drug.…”

Targeting the cutaneous microbiota in atopic dermatitis: ‘A new hope’ or ‘attack of the CoNS’?

“…In this issue of Clin Transl Med, Weiss et al. 8 investigated the potency and the spectrum of ATx201 (niclosamide) in pre‐clinical models and further analysed its propensity for resistance evolution. The impact of ATx201 OINTMENT 2% on the skin microbiome and load of S. aureus was then assessed in a clinical trial in patients with mild‐to‐severe AD.…”

“…In a Phase II trial of 36 patients with mild‐to‐severe AD, they showed that patients receiving ATx201 OINTMENT 2% twice daily had a significant reduction in the abundance of S. aureus and increasing Shannon diversity of skin microbiome compared to vehicle after 7 days. 8 However, the impact of ATx201 on the healthy skin microbiota and specificity of ATx201's effect to S. aureus remains to be fully elucidated. Accordingly, higher‐resolution metagenomics and longer treatment duration such as 28, 42 or 84 days are still needed along with approaches to quantitate whether increases in Shannon diversity result primarily from a reduction in S. aureus or a regrowth of the commensal microbiota.…”

“…In this issue of Clin Transl Med, Weiss et al 8 . investigated the potency and the spectrum of ATx201 (niclosamide) in pre‐clinical models and further analysed its propensity for resistance evolution.…”