VISIBLE: pioneering transcriptomic analysis of psoriasis in skin of color

Summary: VISIBLE is an ongoing Phase 3b study of guselkumab (GUS) in participants (pts) with moderate-to-severe plaque psoriasis (PsO) across the entire spectrum of objectively measured skin tones. Pts were randomized 3:1 to receive GUS 100 mg at Week (W) 0, 4, then every 8 W (Q8W), or placebo (PBO) with PBO crossover at W16. Participation in the biopsy substudy was optional. Bulk stranded RNA sequencing (RNA-seq) was performed on both non-lesional (NL) and lesional (LS) skin biopsies at W0 (n=31), and only LS biopsies at W16 (n=27) and W48 (n=20). At W0, 3635 genes (fold change cutoff 2, FDR 0.05) were observed to be differentially expressed in LS vs NL samples. Reduced expression of genes such as<i> IL23A</i>,<i> IL12B</i>,<i> IL23R</i>,<i> IL17A, IL17C, IL17F</i>, <i>IL19</i>, <i>DEFB4A</i>, and <i>S100A7/8/9/11</i> in LS samples from GUS-treated pts was seen by W16 and maintained at W48. Similar patterns were seen in LS samples after PBO→GUS crossover. Following GUS treatment, PsO disease-associated gene sets that showed elevated expression in PsO LS samples at W0 normalized to W0 NL levels. Significant differences in gene expression were observed between Psoriasis Area and Severity Index (PASI) 90 responders (R) vs nonresponders (NR) at W16. In W16 PASI90 NR LS samples, disease-driving gene sets related to Th17 cells, IL22 signaling, and inflamed keratinocytes remained differentially elevated, and less reduction in expression of genes associated with proliferating inflamed keratinocytes and inflammatory myeloid cells modules was seen by single-cell RNA-seq-derived cell type annotation. These gene expression findings in PsO pts with skin of color treated with GUS appear consistent with those in predominantly white PsO cohorts; further studies are needed to confirm these findings. J North¹, Jason Hawkes², B Ungar³, Jordan Talia³, O Choi⁴, Y Chen⁵, H Moncrieffe⁴, Monica W. Leung⁵, R Panchakshari⁵, T Alkousakis⁴, D Chan⁴, George Han³, Aaron Farberg⁶, Shawn Kwatra⁷ 1. UCSF, San Francisco, CA, United States. 2. Oregon Medical Research Ctr, Portland, OR, United States. 3. Icahn School of Medicine at Mt Sinai, NY, NY, United States. 4. J&J, Horsham & Spring House, PA, United States. 5. J&J, San Diego, CA, United States. 6. Bare Dermatology, Dallas, TX, United States. 7. University of Maryland, Baltimore, MD, United States. Clinical Research: Interventional Research