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      ATI-1777, a Topical Jak1/3 Inhibitor, May Benefit Atopic Dermatitis without Systemic Drug Exposure: Results from Preclinical Development and Phase 2a Randomized Control Study ATI-1777-AD-201

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          Abstract

          Introduction

          Atopic dermatitis, a chronic, pruritic skin disease, affects 10–30% of children and up to 14% of adults in developed countries. ATI-1777, a potent and selective Jak1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited Jak1/3 with limited systemic exposure and without any adverse effects.

          Primary objective

          The primary goal of this study was to assess the preliminary clinical efficacy of ATI-1777 topical solution in adults with moderate or severe atopic dermatitis.

          Design

          ATI-1777-AD-201, a phase 2a, first-in-human, randomized, double-blind, vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48 participants with atopic dermatitis over 4 weeks.

          Primary endpoint

          The primary endpoint was a reduction of a modified Eczema Area and Severity Index score from baseline.

          Results

          Reduction was significantly greater in the ATI-1777–treated group on day 28 than in vehicle-treated group (percentage reduction from baseline = 74.45% [standard error = 6.455] and 41.43% [standard error = 6.189], respectively [ P < .001]). Average plasma concentrations of ATI-1777 were <5% of the half-maximal inhibitory concentration of ATI-1777 for inhibiting Jak1/3. No deaths or serious adverse events were reported.

          Conclusion

          Topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of atopic dermatitis.

          Trial Registration

          The study was registered at ClinicalTrials.gov with the number NCT04598269.

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          Most cited references20

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          edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

          Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org). Contact: mrobinson@wehi.edu.au
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            GAGE: generally applicable gene set enrichment for pathway analysis

            Background Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs. Results To address these limitations, we present a new GSA method called Generally Applicable Gene-set Enrichment (GAGE). We successfully apply GAGE to multiple microarray datasets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better results when compared to two other commonly used GSA methods of GSEA and PAGE. We demonstrate this improvement in the following three aspects: (1) consistency across repeated studies/experiments; (2) sensitivity and specificity; (3) biological relevance of the regulatory mechanisms inferred. GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies. From two published lung cancer data sets, GAGE derived a more cohesive and predictive mechanistic scheme underlying lung cancer progress and metastasis. For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT signaling, Wnt signaling, and estrogen signaling pathways–all of which are supported by the experimental literature. Conclusion GAGE is generally applicable to gene expression datasets with different sample sizes and experimental designs. GAGE consistently outperformed two most frequently used GSA methods and inferred statistically and biologically more relevant regulatory pathways. The GAGE method is implemented in R in the "gage" package, available under the GNU GPL from .
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              Adverse effects of topical glucocorticosteroids.

              Topical corticosteroids were introduced into medicine about 50 years ago. They represent a significant milestone in dermatologic therapy. Despite encouragement to report observed adverse drug reactions, the clinical practice of reporting is poor and incomplete. Likewise, adverse effects and safety of topical corticosteroids are neglected in the medical literature. The authors provide an updated review of their adverse-effect profile. Children are more prone to the development of systemic reactions to topically applied medication because of their higher ratio of total body surface area to body weight. Cutaneous adverse effects occur regularly with prolonged treatment and are dependent on the chemical nature of the drug, the vehicle, and the location of its application. The most frequent adverse effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with lower frequency include hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections. Of particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher than generally believed. Systemic reactions such as hyperglycemia, glaucoma, and adrenal insufficiency have also been reported to follow topical application. The authors provide an updated review of local and systemic adverse effects upon administration of topical corticosteroids, including the latest FDA report on the safety of such steroids in children. At the completion of this learning activity, participants should be familiar with topical corticosteroids and their proper use.
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                Author and article information

                Contributors
                Journal
                JID Innov
                JID Innov
                JID Innovations
                Elsevier
                2667-0267
                28 November 2023
                March 2024
                28 November 2023
                : 4
                : 2
                : 100251
                Affiliations
                [1 ]Aclaris Therapeutics, Chesterbrook, Pennsylvania, USA
                [2 ]Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
                [3 ]Miguel Hernández University of Elche, Alicante, Spain
                [4 ]Research and Development, Context Therapeutics, Philadelphia, Pennsylvania, USA
                [5 ]Raoof MD Dermatology, Encino, California, USA
                [6 ]CenExel FCR, Tampa, Florida, USA
                [7 ]Clinical Development, Immunology, Johnson & Johnson, West Chester, Pennsylvania, USA
                Author notes
                []Correspondence: Paul Changelian, Aclaris Therapeutics, 701 Lee Road, Chesterbrook, Pennsylvania 19087, USA. pchangelian@ 123456aclaristx.com
                Article
                S2667-0267(23)00077-2 100251
                10.1016/j.xjidi.2023.100251
                10825549
                38299059
                f36b6e5e-35c3-44d0-8723-7bda1a68f21e
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 27 July 2022
                : 16 October 2023
                : 3 November 2023
                Categories
                Original Article

                hematopoiesis,metabolism,porcine model,screening,skin
                hematopoiesis, metabolism, porcine model, screening, skin

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