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      Efficacy and safety of PAC‐14028 cream – a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild‐to‐moderate atopic dermatitis: a phase IIb randomized trial†

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          Summary

          Background

          Transient receptor potential vanilloid subfamily, member 1 ( TRPV1) may play an important role in pruritus and inflammation induction in atopic dermatitis ( AD). The treatment effect of TRPV1 antagonist via topical application in patients with AD remains unknown.

          Objectives

          To assess the clinical efficacy and safety of PAC‐14028, a TRPV1 antagonist, via topical application in patients with AD.

          Methods

          In this 8‐week, phase IIb, randomized, double‐blind, multicentre, vehicle‐controlled study, patients with mild‐to‐moderate AD were randomized to receive PAC‐14028 cream 0·1%, 0·3%, 1·0% or vehicle cream twice daily. The primary efficacy end point was the Investigator's Global Assessment ( IGA) success rate defined as the percentage of patients with an IGA score of 0 or 1 at week 8. The secondary efficacy end points included the severity Scoring of Atopic Dermatitis ( SCORAD) index and Eczema Area and Severity Index ( EASI) 75/90.

          Results

          A total of 194 patients were enrolled. IGA success rates at week 8 were 14·58% for vehicle cream, 42·55% for PAC‐14028 cream 0·1% ( P = 0·0025 vs. vehicle), 38·30% for PAC‐14028 cream 0·3% ( P = 0·0087 vs. vehicle) and 57·45% for PAC‐14028 cream 1·0% ( P < 0·001 vs. vehicle). In particular, statistically significant differences were found between the vehicle and treatment groups in the IGA success rates with two‐grade improvement. The SCORAD index, EASI 75/90, sleep disturbance score and pruritus visual analogue scale showed a trend towards improvement. No significant safety issues were reported.

          Conclusions

          PAC‐14028 cream may be an effective and safe treatment modality for the treatment of patients with mild‐to‐moderate AD.

          Abstract

          What is already known about this topic?

          • Atopic dermatitis ( AD) is one of the most common inflammatory skin diseases characterized by pruritic erythematous skin lesions and barrier dysfunction.

          • Transient receptor potential vanilloid subfamily, member 1 ( TRPV1) antagonists suppress the release of pruritic and proinflammatory mediators.

          • The preclinical results demonstrate the feasibility of TRPV1 as a potential therapeutic target for the treatment of AD.

          What does this study add?

          • TRPV1 regulates inflammation and pruritus in patients with AD.

          • PAC‐14028 cream, a novel TRPV1 antagonist, was superior to vehicle in improving clinical symptoms and signs with a favourable safety profile in adults with mild‐to‐moderate AD.

          • TRPV1 antagonism may play a role as a promising nonsteroidal topical treatment target for AD with a new mechanism of action.

          Linked Editorial: https://doi.org/10.1111/bjd.17777.

          https://doi.org/10.1111/bjd.17802 available online

          https://www.bjdonline.com/article/

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          Most cited references24

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          Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis.

          A-M Calza, R Lever, DJ Atherton … (1993)
          Assessment methods for atopic dermatitis (AD) are not standardized, and therapeutic studies are difficult to interpret. To obtain a consensus on assessment methods in AD and to use a statistical method to develop a composite severity index. Consensus definitions were given for items used in the scoring system (extent, intensity, subjective) and illustrated for intensity items. Slides were reviewed to address within- and between-observer variability by a group of 10 trained clinicians, and data were statistically evaluated with a two-way analysis of variance. Two variants of an assessment system were compared in 88 patients at 5 different institutions. Data were analyzed using principal-component analysis. For 5 intensity items studied (erythema, edema/papulation, oozing/crusts, excoriations, lichenification), within- and between-observer variability was good overall, except for edema/papulation which was difficult to assess with slides. In the series of 88 patients, principal-component analysis allowed to extract two unrelated components: the first one accounting for 33% of total variance was interpreted as a 'severity' component; the second one, accounting for 18% of variance, was interpreted as a 'profile' component distinguishing patients with mostly erythema and subjective symptoms and those with mostly lichenification and dryness and lower subjective symptoms. Of the two evaluation systems used, the one using the rule of nine to assess extent was found more workable than the one using a distribution x intensity product. A scoring index (SCORAD) combining extent, severity and subjective symptoms was mathematically derived from the first system and showed a normal distribution of the population studied. The final choice for the evaluation system was mostly made based on simplicity and easy routine use in outpatient clinics. Based on mathematical appreciation of weights of the items used in the assessment of AD, extent and subjective symptoms account for around 20% each of the total score, intensity items representing 60%. The so-designed composite index SCORAD needs to be further tested in clinical trials.
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            A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1.

            Terhi S Savinko, Tasuku Akiyama, Akihiko Ikoma … (2014)
            Although the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear. We sought to determine whether immune cell-derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31-induced itch. We used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects. Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31-induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)-deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca(2+) release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo. IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
            Article 0 comments Cited 214 times – based on 0 reviews     Review now
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              The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.

              Susan Tofte, J Hanifin, T Omoto … (2001)
              To test the reliability of the eczema area and severity index (EASI) scoring system by assessing inter- and intra-observer consistency. Training of evaluators, application, and assessment over 2 consecutive days. An academic center. Twenty adults and children with atopic dermatitis (AD); cohort 1 (10 patients > or = 8 years) and cohort 2 (10 patients < 8 years). None. The EASI was used by 15 dermatologist evaluators to assess atopic dermatitis in cohort 1 and cohort 2 on 2 consecutive days. Inter- and intraobserver reliability were analyzed. Overall intra-evaluator reliability of the EASI was in the fair-to-good range. Inter-evaluator reliability analyses indicated that the evaluators assessed the patients consistently across both study days. This study demonstrated that the EASI can be learned quickly and utilized reliably in the assessment of severity and extent of AD. There was consistency among the evaluators between consecutive days of evaluation. These results support the use of the EASI in clinical trials of therapeutic agents for AD.
              Article 0 comments Cited 186 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                M. Park:
                ORCID: https://orcid.org/0000-0003-3598-5420
                mypark@amorepacific.com
                B. Kim: beomjoon74@gmail.com
                Journal
                Journal ID (nlm-ta): Br J Dermatol
                Journal ID (iso-abbrev): Br. J. Dermatol
                Journal ID (doi): 10.1111/(ISSN)1365-2133
                Journal ID (publisher-id): BJD
                Title: The British Journal of Dermatology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0007-0963
                ISSN (Electronic): 1365-2133
                Publication date (Electronic): 08 January 2019
                Publication date (Print): May 2019
                Volume: 180
                Issue: 5 ( doiID: 10.1111/bjd.2019.180.issue-5 )
                Pages: 1030-1038
                Affiliations
                [ 1 ] Department of Dermatology Konkuk University School of Medicine Seoul Republic of Korea
                [ 2 ] Department of Dermatology Ulsan University College of Medicine Asan Medical Center Seoul Republic of Korea
                [ 3 ] Vital Beautie Research Institute AmorePacific Corporation R&D Center Yongin Republic of Korea
                [ 4 ] Department of Dermatology Chung‐Ang University College of Medicine Seoul Republic of Korea
                Author notes
                [*] [* ] Correspondence

                Beomjoon Kim.

                E‐mail: beomjoon74@ 123456gmail.com

                Miyoung Park.

                E‐mail: mypark@ 123456amorepacific.com

                Author information
                https://orcid.org/0000-0003-3598-5420
                Article
                Publisher ID: BJD17455
                DOI: 10.1111/bjd.17455
                PMC ID: 6850419
                PubMed ID: 30623408
                SO-VID: b5d7cf0d-4f21-48ad-8678-32ba55e92986
                Copyright © © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date accepted : 26 November 2018
                Page count
                Figures: 5, Tables: 2, Pages: 9, Words: 5761
                Funding
                Funded by: AmorePacific Corp.
                Categories
                Subject: Clinical Trial
                Subject: Original Articles
                Subject: Clinical Trial
                Custom metadata
                source-schema-version-number 2.0
                cover-date May 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:12.11.2019

                ScienceOpen disciplines: Dermatology
                Data availability:
                ScienceOpen disciplines: Dermatology

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