TRIV-509, a dual inhibitor of KLK5 and KLK7, rapidly improves barrier integrity and markers of epidermal differentiation in atopic dermatitis skin explants

Summary: Impaired barrier integrity and disordered epidermal differentiation are hallmarks of atopic dermatitis (AD). KLK5 and KLK7, serine proteases involved in the natural desquamation process, are dysregulated in AD and contribute to these pathologies along with independently driving inflammation (KLK5-PAR2 pathway) and itch (KLK7-dependent pathway). In diseased skin, KLK5 and KLK7 are hyperactive and aberrantly expressed in layers below the <i>stratum corneum</i>, where they can cleave crucial epidermal structural proteins such as DSG1, DSC1, CDSN. Cleavage of essential junctional proteins permits penetration of allergens, irritants, and bacteria which triggers a vicious cycle of inflammation, pruritus, and further barrier loss. TRIV-509 is a dual-targeting monoclonal antibody, in early clinical development for AD, that potently and selectively inhibits KLK5 and KLK7. To further elucidate the mechanism of KLK5 and KLK7 inhibition in AD, lesional and/or peri-lesional biopsies were collected from 3 patients with a clinical diagnosis of AD (IGA (Investigators Global Assessment) <u>></u>2) and treated with TRIV-509 or vehicle control <i>ex vivo</i>. After 72 hours, the biopsies were processed for histological and protein analysis. In all three patients, TRIV-509 significantly reduced epidermal thickness and parakeratosis in active AD skin. Furthermore, TRIV-509 blunted (<u>></u>80% reduction) cell proliferation in the epidermis as measured by Ki-67. Finally, TRIV-509 significantly increased the number of DSG1+ cells in the appropriate layers of the epidermis. Together this data demonstrates that KLK5 and KLK7 inhibition rapidly improves the barrier integrity and markers of epidermal differentiation <i>ex vivo</i>, thereby highlighting the therapeutic potential of TRIV-509 in AD. Elizabeth Mateer¹, Eva Asp¹, Marta Silva e Sousa², Ilaria Piccini², Janin Edelkamp², Bhaskar Srivastava¹, Jennifer Dovey¹ 1. Triveni Bio, Watertown, MA, United States. 2. QIMA Monasterium GmbH, QIMA Life Sciences, Münster, Germany. Translational Studies: Preclinical