Spatial profiling identifies distinct patterns of immune modulation with dupilumab in the dermis and epidermis of atopic dermatitis patients with improved quality of life

Summary: Abstract Body: Epidermal and dermal responses in atopic dermatitis (AD) to dupilumab are poorly understood. GeoMx™ Digital Spatial Profiling was undertaken on skin biopsies collected as part of a phase 4, open-label, exploratory study in 31 adults with moderate-to-severe AD receiving dupilumab 300 mg every 2 weeks for 16 weeks and on skin biopsies collected from 10 healthy controls. The SCOring Atopic Dermatitis (SCORAD) index decreased by 75% (90% confidence limits: −83 to −62.3%, P < 0.0001). Spatial profiling highlighted a significant reduction in IL-4R expression in both the epidermis (−6%, P [adj] = < 8.48×107) and dermis (−4, P [adj] = 0.03), while IL-13Rα significantly decreased in only the epidermis (−6%, P [adj] = 0.0019). There was overlap in PCA transcriptional profiles between the post-treatment and healthy samples, which clustered separately from pre-treatment samples. Gene sets in Notch signaling, interferon signaling, and cell cycle pathways were significantly reduced in the epidermis, while gene sets associated with IL-4, IL-13, cytokine, and chemokine signaling were significantly reduced in the dermis. There were a number of significantly differentially expressed genes associated with changes in itch (Peak Pruritus-NRS) and intraepidermal nerve fiber density. Dupilumab normalizes canonical and non-canonical pro-inflammatory pathways associated with improvement in itch in the epidermis and dermis of AD patients. Nicholas P. West¹, Leigh A. Nattkemper², Sarah Williams³, Amanda J. Cox¹, Jean Barcelon¹, James Sinclair¹, Peter K. Smith¹, Konstantin Agelopoulos⁴, Sonja Staender⁴, Felix Whitte⁴, Madison R. Mack⁵, Joseph Zahn⁶, Annie Zhang⁷, Gil Yosipovitch² 1. Griffith University, Southport, QLD, Australia. 2. University of Miami Miller School of Medicine, Miami, FL, United States. 3. The University of Queensland, Brisbane, QLD, Australia. 4. University Hospital Muenster, Muenster, Muenster, Germany. 5. Immunology & Inflammation Research, Sanofi, Cambridge, MA, United States. 6. Regeneron Pharmaceuticals Inc, Tarrytown, NY, United States. 7. Medical Affairs, Sanofi, Cambridge, MA, United States. Clinical Research: Interventional Research