A Phase 1b, Randomized, Single-Center Trial of Topical Cerdulatinib (DMVT-502) in Patients with Mild-to-Moderate Atopic Dermatitis

Cerdulatinib (DMVT-502) is an investigational kinase inhibitor with demonstrated activity against Jak and SYK (Coffey et al., 2014Coffey G. Betz A. DeGuzman F. Pak Y. Inagaki M. Baker D.C. al.The novel PRT062070 (cerdulatinib) demonstrates efficacy in models of autoimmunity B-cell cancer.J Pharmacol Exp Ther. 2014; 351: 538-548Crossref PubMed Scopus (51) Google Scholar). There are currently no FDA approved topical Jak/SYK inhibitors for the treatment atopic dermatitis (AD). Preclinically, cerdulatinib gel (0.2% 0.4%, representing 0.18% 0.37% free base, respectively) was shown to improve epidermal hyperplasia, inflammatory cell infiltration, hyperkeratosis AD mouse model (McHale 2018McHale K. Harrington W. Roeloffs R. Lee J. Effect RVT-502 therapy NC/Nga dermatitis.J Investig Dermatol. 2018; 138: S184Abstract Full Text PDF This study designed evaluate safety, activity, target engagement patients mild-to-moderate AD. phase 1b, single-center, double-blind evaluated safety its effect on molecular profile lesional (LS) skin adults (inclusion exclusion criteria Supplementary Table S1). All provided written informed consent. The conducted compliance Good Clinical Practice guidelines Declaration Helsinki reviewed by IRB Services, Aurora, Ontario, Canada. Study design, methods, materials Figure S1, Materials Methods, Tables S1–S3. Patients (N = 10) were randomized at 4:1 twice-daily application or vehicle 14 days (Supplementary S2). In group (n 8; female 4), mean age 30.8 years, baseline (SD) Eczema Area Severity Index (EASI) 4.0 (2.0), body surface area affected 4.3% pruritus numeric rating scale score 4.4 (1.8). 2; 2), 23.5 EASI 2.4 (0.8), 3.0% (0.0), 1.5 (2.1). Baseline demographics disease characteristics summarized S4. Overall, 8 10 experienced 35 treatment-emergent adverse events that all mild (34 35; 97%) moderate (1 3%). Headache most common event, occurring 3 group. Two both groups reported categorized as general disorders administration-site conditions, 1. No clinically significant effects vital signs electrocardiograms observed, discontinued because events.Table 1Summary TEAEs General Disorders Administration-Site Conditions Reported during Period (from Day 1 14)TEAE Preferred Term, n (%)Cerdulatinib Gel 8)Vehicle 2)Any TEAE, n2510Patients ?1 TEAE6 (75)2 (100)Patients drug-related TEAE5 (63)2 (100)TEAE severity Grade 1/mild24 (96)10 (100) 2/moderate1 (4)0General conditions2 (25)2 Application-site discoloration1 (13)0 erythema0 (0)1 (50) pruritus1 (13)1 reaction1 Feeling cold1 (13)0Abbreviation: event. Open table a new tab Abbreviation: After gel, scores decreased from change –2.6 (1.4), which statistically (P < 0.001). who received (Figure 1a). Mean groups, but not S5). exploratory analysis, LS biopsies obtained (day 1) after compare changes thickness, cellular gene expression before treatment. Biopsies vehicle-treated assessed small number this Epidermal thickness significantly reduced 1b). Keratin 16 protein 7 Ki67+ cells 0.05) treatment, supported keratin 16, K16, mRNA S3). Accumulation CD11c+ myeloid dendritic 1c) CD206+ 1d) 0.01 P 0.001, respectively). Decreases CD3+ T Fc?RI+ significant, may be due sample size short duration. major basic protein-positive eosinophil counts increase Langerin-positive Langerhans RNA sequencing performed Fold >2.0 0.05 used define differentially expressed genes false discovery rate–adjusted values limited S6). 1,047 identified S4), included upregulation related lipid metabolism, differentiation, tight-junction products (CDH20; KRT77 CLDN8; LPIN1) downregulation associated inflammation (matrix metalloproteinase 12 MMP12), innate immunity (IL-6 IL-8/CXCL8), helper type (Th)1 (OASL), Th2 (CCL3), Th17- Th22 (PI3/elafin, CXCL1, S100A7/A8/A9/A12, IL-20)-related 1e). Gene set variation analysis pathways induced keratinocytes IL-17 alone combination IL-22 TNF-? Th22- IL-22?related Quantitative real-time reverse transcriptase–PCR validate findings assess have low detection levels sequencing. including (IL-5, IL-10, CCL13), Th17 (IL-19, PI3/elafin, CXCL2), and/or (S100A7/S100A8/S100A9/S100A12) (all 0.05; other biomarkers, CXCL9, IL-13, IL-22, terminal differentiation markers, been duration study. clinical improvements key markers skin. correlated IL-23p40 (Spearman correlation coefficient [?] 0.74; 0.046); involvement IL-15 (? 0.90; 0.002), IL-10 0.76; 0.030), IL-32 0.73; 0.039) expression; IL-23p19 0.83; 0.0099) Figures S7 S8). These suggest improvement AD, itch, Th17/Th22 pathway (Noda 2015Noda S. Suárez-Fariñas Ungar B. Kim S.J. de Guzman Strong C. Xu H. Asian phenotype combines features psoriasis increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract (318) Scholar; Renert-Yuval Guttman-Yassky, 2020Renert-Yuval Guttman-Yassky E. New treatments targeting beyond IL-4/IL-13 cytokines.Ann Asthma 2020; 124: 28-35Abstract (62) full list Spearman correlations day S8. Topical well-tolerated few events, although powered efficacy, improved days. various mediators attributed broad Jak/signal transducer activator transcription signal transduction multiple (Brunner 2017Brunner P.M. Leung D.Y. immunology reversibility broad-spectrum targeted therapies.J 2017; 139: S65-S76Abstract (304) Villarino 2017Villarino A.V. Kanno O’Shea J.J. Mechanisms consequences Jak-STAT signaling immune system.Nat 18: 374-384Crossref (520) Yasukawa 2014Yasukawa Miyazaki Yoshii Nakaya Ozaki N. Toda al.An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity stimulating IL-1 production cells.Nat Commun. 5: 3755Crossref (60) Emollient use permitted partially contributed observed. 1b cerdulatinib, size. support need larger studies responses warrant further investigation. data available Expression Omnibus (accession number: GSE141570) https://www.ncbi.nlm.nih.gov/geo/. remaining proprietary publicly available. made reasonable request permission Dermavant Sciences (Durham, NC) marketing approval obtained, restrictions will apply availability these data. Stephen Piscitelli: http://orcid.org/0000-0002-4528-3273 Ana Pavel: http://orcid.org/0000-0002-0497-8351 Kimberly McHale: http://orcid.org/0000-0003-3292-5772 John Jett: http://orcid.org/0000-0002-1940-457X Jon Collins: http://orcid.org/0000-0002-2929-3500 Dawn Gillmor: http://orcid.org/0000-0002-8622-0682 Glenn Tabolt: http://orcid.org/0000-0002-9668-8270 Randall Li: http://orcid.org/0000-0002-7504-0723 Teresa Song: http://orcid.org/0000-0002-1507-9933 Ning Zhang: http://orcid.org/0000-0002-9754-1561 Anna Tallman: http://orcid.org/0000-0001-9535-0414 Emma Guttman-Yassky: http://orcid.org/0000-0002-9363-324X SCP, KM, JEJ, GT, AMT employees stock options. JC employee Immunovant options has GlaxoSmithKline Roivant Sciences. DG Enzyvant ABP NZ Mount Sinai. EGY Sinai research funds (grants paid institution) AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boehringer Ingelheim, Celgene, Sciences, DS Biopharma, Eli Lilly, Glenmark, Galderma, Innovaderm Research, Janssen, Kiniska Pharmaceuticals, Kyowa Kirin, Leo Pharma, Novan, Pfizer, Ralexar Therapeutics, Regeneron, Sienna UCB, Union Therapeutics. also consultant Cara Concert, DBV Technologies, Dermira, EMD Serono, Escalier, Mitsubishi Tanabe, RAPT Sanofi, authors state conflict interest. We thank participating investigators, patients, their families well colleagues involved conduct Editorial medical writing under guidance Yee-Man Ching ApotheCom, London, United Kingdom funded accordance Publication (Ann Intern Med 2015;163:461–464). one center Conceptualization: EGY; Data Curation: ABP; Formal Analysis: ABP, AMT; Funding Acquisition: Investigation: Methodology: NZ, Project Administration: JC, DG, Resources: Software: Supervision: Validation: Visualization: RL, TS; Writing - Original Draft Preparation: AMT, Review Editing: TS, Download .pdf (5.78 MB) Help pdf files Suppl .csv (1.0 csv S2