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