Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: A double-blind Phase Ib study

Abstract

The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double-blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions. Two lesions from each participant (n = 11) were each randomized to topical application of 1% (w/w) GSK2646264 or placebo for 28 days; all participants received GSK2646264 and placebo. The primary endpoint was safety and tolerability of GSK2646264, assessed by adverse event incidence and a skin tolerability test. Secondary endpoints included change from baseline in clinical activity and mRNA expression of interferon-related genes in skin biopsies. Levels of several immune cell markers were evaluated over time. Eight (73%) participants experienced ≥ 1 adverse event (all mild in intensity), and maximal dermal response was similar for GSK2646264 and placebo. The expression of several interferon-related genes, including CXCL10 and OAS1, showed modest decreases from baseline after 28 days of treatment with GSK2646264 compared with placebo. Similar findings were observed for CD3 + T cell and CD11c + dendritic cell levels; however, overall clinical activity remained unchanged with GSK2646264 vs. placebo. Further studies are warranted to assess SYK inhibitors as potential treatment for CLE.

Trial registration: ClinicalTrials.gov NCT02927457.

Keywords: SYK Kinase; cutaneous lupus erythematosus; interferons; pharmacology; safety.

Conflict of interest statement

AW, KF, KN, NW, NR, BH, TSM, SG and HC are employees of GSK and hold stocks/shares in GSK. LE and MD were employees of GSK at the time of the study. JW reports grants from GSK, grants from Incyte, personal fees from Biogen, personal fees from Leo Pharma and other from Novartis. MW received honoraria for consulting by ALK‐Abelló Arzneimittel GmbH, Mylan Germany GmbH, Bencard Allergie GmbH, Novartis AG, Biotest AG, Actelion Pharmaceuticals Deutschland GmbH, Sanofi‐Aventis Deutschland GmbH and HAL Allergie GmbH.

© 2020 Glaxo Group Limited. Experimental Dermatology published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Adjusted mean (95% CI) intensity of log2 mRNA expression by visit and treatment (A) CXCL10, (B) IFI44, (C) IFIH1, (D) OAS1, (E) IL1A, (F) IL1B, and (G) IL6, (H) IFI16, (I) IFI44L, (J) IFIT1 and (K) IFIT3. For genes that had more than one probe analysed, the probe that showed the largest treatment difference is shown. Adjusted mean intensity values were derived using a mixed model with participant as a random effect and treatment as a fixed effect where treatment is set to “not applicable” at baseline. CI, confidence interval

FIGURE 2

Mean (±SE) expression (cells/mm2) of (A) CD3 + T cells and (B) CD11c + dendritic cells in the dermis from biopsies by visit, treatment and sub‐acute/chronic CLE subtypes. Immunohistochemical staining (C) of CD3 + T cells (i–v, xi–xv) and CD11C + dendritic cells (vi–x, xvi–xx) in CLE skin samples in the presence and absence of GSK2646264 treatment from two representative participants. Images represent uninvolved (i, vi, xi, xvi), baseline placebo (ii, vii, xii, xvii), baseline GSK2646264 (iii, viii, xiii, xviii), placebo‐treated at Day 28 (iv, ix, ixv, ixx) and GSK2646264‐treated (x, v, xv, xx) at Day 28. Yellow staining = CD3/CD11c; blue staining = haematoxylin; green = overlap of yellow and blue staining. Scale bars denote 200 µm. Images from Participant #8 and Participant #9 are included as representative images for participants in which immunohistochemical staining changes were and were not observed, respectively. CLE, chronic lupus erythematosus; SE, standard error